Improved safety margin for embryotoxicity in rats for the new endoperoxide artefenomel (OZ439) as compared to artesunate
Autor: | Monica Longo, Jon Rhodes, Thomas Rückle, Joseph Kinney, Robert L. Clark, Don K. Walker, Anna Christine Huber, Tammye L. Edwards, Timothy N. C. Wells, Nicole Andenmatten, Sally Clode |
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Rok vydání: | 2017 |
Předmět: |
0301 basic medicine
Embryology Organogenesis Health Toxicology and Mutagenesis medicine.medical_treatment 030231 tropical medicine Artesunate Dihydroartemisinin Adamantane Gestational Age Phthalimides Heme Pharmacology Toxicology Fetal Development Antimalarials 03 medical and health sciences chemistry.chemical_compound Organ Culture Techniques 0302 clinical medicine In vivo Animals Medicine Toxicokinetics Artemisinin Active metabolite Dose-Response Relationship Drug business.industry Embryo Mammalian Artemisinins Benzoxazines Peroxides Rats 030104 developmental biology chemistry Pediatrics Perinatology and Child Health Toxicity Female business Developmental Biology Toxicant medicine.drug |
Zdroj: | Birth Defects Research. 110:553-578 |
ISSN: | 2472-1727 |
DOI: | 10.1002/bdr2.1170 |
Popis: | Background Combination medicines including an artemisinin are the mainstay of antimalarial therapy. Artemisinins are potent embryotoxicants in animal species due to their trioxane moiety. Methods As part of its development, the new synthetic trioxolane antimalarial artefenomel (OZ439) was tested in rat whole embryo culture and in rat embryo-fetal toxicity studies with dosing throughout organogenesis or with a single dose on Gestational Day (GD) 12. The single-dose studies included groups treated with artesunate to allow a direct comparison of the embryotoxicity of the two antimalarials and included toxicokinetics hematology and histological examination of embryos. In addition, the distribution of artefenomel-related material in plasma was determined after the administration of 14 C-artefenomel. Results Artefenomel and artesunate showed similar patterns of embryotoxicity including cardiovascular defects and resorption with a steep dose-response. They both also caused a depletion of circulating embryonic erythroblasts both in vitro and in vivo and decreases in maternal reticulocyte count. However, artefenomel was ∼250-fold less potent than the active metabolite of artesunate (dihydroartemisinin) as an embryotoxicant in vitro. The safety margin (based on AUC) for artefenomel administered on GD 12 was approximately 100-fold greater than that for artesunate. Also, unlike artesunate, artefenomel was not a selective developmental toxicant. Conclusions The lesser embryotoxicity of artefenomel is likely linked to its original design which included two blocking side groups that had been introduced to lower the reactivity with ferrous iron. Our data support the hypothesis that artefenomel's improved safety margin is linked to a lower potential for inhibiting heme biosynthesis in embryonic erythroblasts. |
Databáze: | OpenAIRE |
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