Diflunisal-induced maternal anemia as a cause of teratogenicity in rabbits
Autor: | Robert L. Clark, David H. Minsker, Mary L. James, Sheila M. Cohen, Richard T. Robertson, Henry L. Allen, Bokelman Dl, Dominick J. Tocco |
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Rok vydání: | 1984 |
Předmět: |
Hemolytic anemia
Embryology medicine.medical_specialty Anemia Hemolytic Erythrocytes Anemia Health Toxicology and Mutagenesis Analgesic Diflunisal Gestational Age Toxicology Antioxidants Adenosine Triphosphate Pregnancy Placenta Internal medicine medicine Animals Maternal-Fetal Exchange Aspirin business.industry Pregnancy Complications Hematologic Abnormalities Drug-Induced Rats Inbred Strains Hypoxia (medical) medicine.disease Salicylates Rats Endocrinology medicine.anatomical_structure Anesthesia Gestation Female Rabbits medicine.symptom business Developmental Biology medicine.drug |
Zdroj: | Teratology. 30(3) |
ISSN: | 0040-3709 |
Popis: | Diflunisal [5-(2,4-difluorophenyl)-salicylic acid] is a new analgesic antiinflammatory drug that, when administered orally to rabbits at 40 and 60 mg/kg/day, caused terata, most commonly axial skeletal defects. These same dosage levels also caused a severe maternal hemolytic anemia following a dramatic decrease in erythrocyte ATP levels. The teratogenicity, anemia, and depletion of ATP were unique to the rabbit among species examined. To test the possible causality between the teratogenic effects and anemia induced by diflunisal, a single dose of 180 mg/kg diflunisal was administered to rabbits on gestation day 5. This treatment produced an anemia that persisted through gestation day 15 in addition to causing the characteristic axial skeletal defects. Since diflunisal was cleared from maternal blood before gestation day 9, the critical day for induction of similar axial skeletal defects by hypoxia, the skeletal malformations probably resulted from maternal hypoxia secondary to anemia and not from a direct and specific effect of the drug on the embryo. In addition, we observed that the diflunisal level in the embryo was less than 5% of the peak maternal blood level probably as a result of high plasma protein binding of diflunisal in the maternal blood (greater than 98%). This relatively low placental transfer may explain the lack of diflunisal teratogenicity in rats and mice compared to aspirin which crosses the placenta more readily. These studies demonstrate that a species that exhibits unusually severe drug-specific maternotoxicity is probably an unsuitable model for the prediction of the teratogenic potential of that drug in humans. |
Databáze: | OpenAIRE |
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