title: Combined treatment potentiates the developmental toxicity of ibuprofen and acetazolamide in rats.
abstract: Aspirin (ASA), an irreversible cyclooxygenase (COX) inhibitor, induces ventricular septal defect (VSD) and diaphragmatic hernia (DH) in rat fetuses when administered on gestation days (GDs) 9-10, a critical period for cardiovascular (CV) and midline development. Evaluation of a spectrum of nonsteroidal antiinflammatory drugs (NSAIDs; reversible COX inhibitors) showed that while some NSAIDs induced VSD in rats, none of the NSAIDs evaluated produced DH. In addition to inhibiting COX, ASA also inhibits carbonic anhydrase. The purpose of this study was to determine whether concurrent inhibition of COX and carbonic anhydrase would produce a teratogenic profile that includes both VSD and DH. To inhibit both COX and carbonic anhydrase, ibuprofen (COX inhibitor) and acetazolamide (carbonic anhydrase inhibitor) were coadministered on GDs 9-10. Groups of 20 female Crl:CD(SD)IGS BR rats were given either 300 mg kg(-1) day(-1) ibuprofen, 1000 mg kg(-1) day(-1) acetazolamide, or both (combination of ibuprofen and acetazolamide). Fetuses were evaluated on GD 21 for external and visceral development. Ibuprofen induced VSD in 3.7% of fetuses per litter; no defects in appendicular skeletal development were noted. Acetazolamide induced VSD in 5.9% of the fetuses per litter and appendicular defects in 41% of the fetuses per litter. Coadministration of ibuprofen and acetazolamide produced VSD in 18.7% of the fetuses per litter and appendicular defects in 77% of the fetuses per litter; however, there were no DH. Therefore, while concurrent inhibition of COX and carbonic anhydrase did not produce DH, potentiation was noted for the induction of VSD and appendicular anomalies.
authors.affiliation: Pfizer Global Research and Development, Groton, Connecticut 06340, USA. Gregg_D_Cappon@Groton.Pfizer.com
authors.forename: Gregg D
authors.initials: GD
authors.lastname: Cappon
authors.forename: T L
authors.initials: TL
authors.lastname: Fleeman
authors.forename: J C
authors.initials: JC
authors.lastname: Cook
authors.forename: M E
authors.initials: ME
authors.lastname: Hurtt
mesh_terms: D000014:Abnormalities, Drug-Induced / Q000209:etiology*; D000086:Acetazolamide / Q000633:toxicity*; D000818:Animals; D000831:Animals, Newborn; D001724:Birth Weight / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002257:Carbonic Anhydrase Inhibitors / Q000633:toxicity*; D016861:Cyclooxygenase Inhibitors / Q000633:toxicity*; D004357:Drug Synergism; D004435:Eating / Q000187:drug effects; D005260:Female; D047109:Fetal Development / Q000187:drug effects; D006345:Heart Septal Defects, Ventricular / Q000139:chemically induced; D006548:Hernia, Diaphragmatic / Q000139:chemically induced; D007052:Ibuprofen / Q000378:metabolism* / Q000633:toxicity; D008297:Male; D018811:Maternal Exposure; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D016861:Cyclooxygenase Inhibitors; D000086:Acetazolamide; D007052:Ibuprofen