Borrallo-Lopez Lucia, Guzman Laura, Romero Noelia G, Sampietro Anna, Mallo-Abreu Ana, Guardia-Escote Laia, Teixidó Elisabet, Flick Burkhard, Fernàndez-Busquets Xavier, Muñoz-Torrero Diego, Barenys Marta
GRET and Toxicology Unit, Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain.
GRET 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, Spain.
Int J Parasitol Drugs Drug Resist. 2025 Apr;27:100582. doi: 10.1016/j.ijpddr.2025.100582. Epub 2025 Jan 22.
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.
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.
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.
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.
孕期疟疾对母亲和发育中的胎儿意味着高风险。然而，孕妇的治疗选择历来非常有限，尤其是在妊娠头三个月，因为可能对胚胎 - 胎儿发育产生潜在不良影响。最近，关于这些潜在的胚胎 - 胎儿不良影响存在很大争议，因为啮齿动物研究结果与现有临床数据不一致，最终世界卫生组织改变了对患有单纯性恶性疟原虫疟疾孕妇的建议，即在妊娠头三个月用蒿甲醚 - 本芴醇治疗。临床前研究和临床研究之间的差异归因于循环原始红细胞易感性窗口持续时间的物种差异。
在此，我们基于一种替代动物实验的方法提供了一种工具，可加速针对孕妇的新型药物研究。我们改进了斑马鱼胚胎发育毒性试验，使其包括胚胎中的血红蛋白染色以及致死率和畸形发生评估的两个时间点。选择这两个时间点是为了包括一个发育独立于红细胞功能的时间点和一个发育依赖于红细胞功能的时间点。该方法用于测试四种市售抗疟药物和三种新的抗疟药物候选物。
我们的测试组合能够正确预测几种市售抗疟药物（青蒿素、奎宁、氯喹以及双氢青蒿素 + 去丁基本芴醇）的致畸和非致畸作用。此外，我们测试了三种具有新作用机制且不同于市售抗疟药物的新药物候选物（GS - GUAN、DONE3TCl 和 YAT2150）。
我们提出了一个决策树，将两个评估时间点的结果与显著红细胞耗竭的信息结合起来。该决策树的目的是在药物开发过程的早期阶段识别出对致畸性或红细胞耗竭无危害或危害较小的化合物。
