Comparison of developmental toxicology of aspirin (acetylsalicylic acid) in rats using selected dosing paradigms.

摘要: Pfizer Global Research and Development, Groton, ConnecticutBACKGROUND: Analysis of the literature for nonsteroidal anti-inflammatory drugs (NSAIDs) suggests that a low incidenceof developmental anomalies occurs in rats given NSAIDs on specific days during organogenesis. Aspirin (acetylsalicylic acid [ASA]),an irreversible cyclooxygenase 1 2 inhibitor, induces when administered to Wistar gestationalday (GD) 9, 10, or 11 (Kimmel CA, Wilson JG, Schumacher HJ. Teratology 4:15–24, 1971). There are no published ASA studies usingthe multiple dosing paradigm GDs 6 17. Objectives current study were compare results between Sprague–Dawley (SD)and strains is GD 11; malformation patterns following single multipledosings organogenesis SD rats; test hypothesis maternal gastrointestinal toxicity confounds detectionof incidence malformations with used. METHODS: was as singledose 9 (0, 250, 500, 625 mg/kg), 10 625, 750 750, 1000 mg/kg) from 17 50,125, 250 mg/kg day) dose rats. Animals killed 21, fetuses examined viscerally.RESULTS: The evaluation suggested induce ventricular septal defects (VSDs) midline (MDs) ratsand diaphragmatic hernia (DH), MDs, VSDs rabbits (Cook JC et al., 2003); hence, present focused thesemalformations, even though several other low-incidence malformations. In studies, DH, MD, VSD wereinduced 10. also noted treatment 11. contrast, DH MD dosestudy design only high-dose group, across all groups. CONCLUSIONS: High concordance majordevelopmental exception hydrocephalus theWistar Variations similar period oforganogenesis (GDs 17). It evident that, by titrating achieve maximum tolerated dose, thatnormally occur at incidence, reported previous could be induced doses.Birth Defects (Part B) 68:27–37, 2003. r 2003 Wiley-Liss, Inc.