Combining the zebrafish embryo developmental toxicity assay (ZEDTA) with hemoglobin staining to accelerate the research of novel antimalarial drugs for pregnant women
Background: Malaria during pregnancy implies a high risk for the mother and the developing child. However, the therapeutic options for pregnant women have historically been very limited, especially during the first trimester of pregnancy due to potential adverse effects on embryo-fetal development....
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Elsevier
2025-04-01
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| Series: | International Journal for Parasitology: Drugs and Drug Resistance |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211320725000053 |
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| author | Lucia Borrallo-Lopez Laura Guzman Noelia G. Romero Anna Sampietro Ana Mallo-Abreu Laia Guardia-Escote Elisabet Teixidó Burkhard Flick Xavier Fernàndez-Busquets Diego Muñoz-Torrero Marta Barenys |
| author_facet | Lucia Borrallo-Lopez Laura Guzman Noelia G. Romero Anna Sampietro Ana Mallo-Abreu Laia Guardia-Escote Elisabet Teixidó Burkhard Flick Xavier Fernàndez-Busquets Diego Muñoz-Torrero Marta Barenys |
| author_sort | Lucia Borrallo-Lopez |
| collection | DOAJ |
| description | Background: Malaria during pregnancy implies a high risk for the mother and the developing child. However, the therapeutic options for pregnant women have historically been very limited, especially during the first trimester of pregnancy due to potential adverse effects on embryo-fetal development. Recently, there has been great controversy regarding these potential embryo-fetal adverse effects because the results of rodent studies were not in accordance with the clinical data available, and finally the WHO has changed the recommendations for pregnant women with uncomplicated P. falciparum malaria to treatment with artemether-lumefantrine during the first trimester. The discrepancy between pre-clinical and clinical studies has been attributed to species-differences in the duration of the window of susceptibility of circulating primitive erythroblasts. Methods: Here we provide a tool based on an alternative method to animal experimentation that accelerates the research of novel drugs for pregnant women. We have adapted the zebrafish embryo developmental toxicity assay to include hemoglobin staining in the embryos and two time-points of lethality and dysmorphogenesis evaluation. These two time-points were selected to include one when the development is independent of and one when the development is dependent of erythrocytes function. The method was used to test four marketed antimalarial drugs and three new antimalarial drug candidates. Results: Our combination of tests can correctly predict the teratogenic and non-teratogenic effects of several antimalarial marketed drugs (artemisinin, quinine, chloroquine, and dihydroartemisinin + desbutyl-lumefantrine). Furthermore, we have tested three new drug candidates (GS-GUAN, DONE3TCl, and YAT2150) with novel mechanisms of action, and different from those of the marketed antimalarial drugs. Conclusions: We propose a decision tree combining the results of the two time-points of evaluation together with the information on significant erythrocyte depletion. The aim of this decision tree is to identify compounds with no or lower hazard on teratogenicity or erythrocyte depletion at an early phase of the drug development process. |
| format | Article |
| id | doaj-art-bda9f3cc21944a59847085647975a8bf |
| institution | DOAJ |
| issn | 2211-3207 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | International Journal for Parasitology: Drugs and Drug Resistance |
| spelling | doaj-art-bda9f3cc21944a59847085647975a8bf2025-08-20T03:08:37ZengElsevierInternational Journal for Parasitology: Drugs and Drug Resistance2211-32072025-04-012710058210.1016/j.ijpddr.2025.100582Combining the zebrafish embryo developmental toxicity assay (ZEDTA) with hemoglobin staining to accelerate the research of novel antimalarial drugs for pregnant womenLucia Borrallo-Lopez0Laura Guzman1Noelia G. Romero2Anna Sampietro3Ana Mallo-Abreu4Laia Guardia-Escote5Elisabet Teixidó6Burkhard Flick7Xavier Fernàndez-Busquets8Diego Muñoz-Torrero9Marta Barenys10GRET and Toxicology Unit, Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, SpainGRET and Toxicology Unit, Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain; Institut de Neurociències, Universitat de Barcelona (UB), Barcelona, Spain; Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED), Instituto de Carlos III, Madrid, SpainGRET and Toxicology Unit, Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain; Institut de Nutrició i Seguretat Alimentària (INSA), Universitat de Barcelona, Barcelona, Spain; Universidad Nacional de Itapua (UNI), ParaguayLaboratory of Medicinal Chemistry (CSIC Associated Unit), Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain; Institut de Biomedicina (IBUB), Universitat de Barcelona, Barcelona, SpainLaboratory of Medicinal Chemistry (CSIC Associated Unit), Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain; Institut de Biomedicina (IBUB), Universitat de Barcelona, Barcelona, SpainGRET and Toxicology Unit, Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, SpainGRET and Toxicology Unit, Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain; Institut de Nutrició i Seguretat Alimentària (INSA), Universitat de Barcelona, Barcelona, SpainDepartment of Toxicology, NUVISAN ICB GmbH, Berlin, GermanyBarcelona Institute for Global Health (ISGlobal, Hospital Clínic-Universitat de Barcelona), Barcelona, Spain; Nanomalaria Group, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Barcelona, Spain; Institut de Nanociència i Nanotecnologia (IN2UB), Universitat de Barcelona, Barcelona, SpainLaboratory of Medicinal Chemistry (CSIC Associated Unit), Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain; Institut de Biomedicina (IBUB), Universitat de Barcelona, Barcelona, SpainGRET and Toxicology Unit, Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain; Institut de Nutrició i Seguretat Alimentària (INSA), Universitat de Barcelona, Barcelona, Spain; German Centre for the Protection of Laboratory Animals (Bf3R), German Federal Institute for Risk Assessmen (BfR), Berlin, Germany; Corresponding author.Background: Malaria during pregnancy implies a high risk for the mother and the developing child. However, the therapeutic options for pregnant women have historically been very limited, especially during the first trimester of pregnancy due to potential adverse effects on embryo-fetal development. Recently, there has been great controversy regarding these potential embryo-fetal adverse effects because the results of rodent studies were not in accordance with the clinical data available, and finally the WHO has changed the recommendations for pregnant women with uncomplicated P. falciparum malaria to treatment with artemether-lumefantrine during the first trimester. The discrepancy between pre-clinical and clinical studies has been attributed to species-differences in the duration of the window of susceptibility of circulating primitive erythroblasts. Methods: Here we provide a tool based on an alternative method to animal experimentation that accelerates the research of novel drugs for pregnant women. We have adapted the zebrafish embryo developmental toxicity assay to include hemoglobin staining in the embryos and two time-points of lethality and dysmorphogenesis evaluation. These two time-points were selected to include one when the development is independent of and one when the development is dependent of erythrocytes function. The method was used to test four marketed antimalarial drugs and three new antimalarial drug candidates. Results: Our combination of tests can correctly predict the teratogenic and non-teratogenic effects of several antimalarial marketed drugs (artemisinin, quinine, chloroquine, and dihydroartemisinin + desbutyl-lumefantrine). Furthermore, we have tested three new drug candidates (GS-GUAN, DONE3TCl, and YAT2150) with novel mechanisms of action, and different from those of the marketed antimalarial drugs. Conclusions: We propose a decision tree combining the results of the two time-points of evaluation together with the information on significant erythrocyte depletion. The aim of this decision tree is to identify compounds with no or lower hazard on teratogenicity or erythrocyte depletion at an early phase of the drug development process.http://www.sciencedirect.com/science/article/pii/S2211320725000053Alternative methods to animal experimentationTeratogenesisNAMsPaludismDrug discoveryToxicity testing |
| spellingShingle | Lucia Borrallo-Lopez Laura Guzman Noelia G. Romero Anna Sampietro Ana Mallo-Abreu Laia Guardia-Escote Elisabet Teixidó Burkhard Flick Xavier Fernàndez-Busquets Diego Muñoz-Torrero Marta Barenys Combining the zebrafish embryo developmental toxicity assay (ZEDTA) with hemoglobin staining to accelerate the research of novel antimalarial drugs for pregnant women International Journal for Parasitology: Drugs and Drug Resistance Alternative methods to animal experimentation Teratogenesis NAMs Paludism Drug discovery Toxicity testing |
| title | Combining the zebrafish embryo developmental toxicity assay (ZEDTA) with hemoglobin staining to accelerate the research of novel antimalarial drugs for pregnant women |
| title_full | Combining the zebrafish embryo developmental toxicity assay (ZEDTA) with hemoglobin staining to accelerate the research of novel antimalarial drugs for pregnant women |
| title_fullStr | Combining the zebrafish embryo developmental toxicity assay (ZEDTA) with hemoglobin staining to accelerate the research of novel antimalarial drugs for pregnant women |
| title_full_unstemmed | Combining the zebrafish embryo developmental toxicity assay (ZEDTA) with hemoglobin staining to accelerate the research of novel antimalarial drugs for pregnant women |
| title_short | Combining the zebrafish embryo developmental toxicity assay (ZEDTA) with hemoglobin staining to accelerate the research of novel antimalarial drugs for pregnant women |
| title_sort | combining the zebrafish embryo developmental toxicity assay zedta with hemoglobin staining to accelerate the research of novel antimalarial drugs for pregnant women |
| topic | Alternative methods to animal experimentation Teratogenesis NAMs Paludism Drug discovery Toxicity testing |
| url | http://www.sciencedirect.com/science/article/pii/S2211320725000053 |
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