Relationship between cyclooxygenase 1 and 2 selective inhibitors and fetal development when administered to rats and rabbits during the sensitive periods for heart development and midline closure

Abstract

Background: A review of the scientific literature suggested the occurrence of low-level incidences of ventricular septal defect (VSD) and midline defect (MD) in rat fetuses and diaphragmatic hernia (DH), VSD, and MD in rabbit fetuses after maternal exposure to nonsteroidal anti-inflammatory drugs (NSAIDs). Aspirin, an NSAID that irreversibly inhibits cyclooxygenase 1 (COX-1) and COX-2, induces DH, VSD, and MD when administered as one dose during the sensitive periods of development in rats. Unlike aspirin, other NSAIDs, including selective COX-2 inhibitors, reversibly inhibit COX activity. To evaluate whether the dysmorphogenesis observed after maternal NSAID exposure correlates with COX-1 or COX-2 inhibition, a series of compounds with different capacities to inhibit COX-1 and COX-2 were administered to pregnant rats and rabbits during the sensitive period for heart development and midline closure.

Methods: The compounds selected, ranked from the most COX-2 selective to the most COX-1 selective based onCOX inhibition in a human whole blood assay, were CJ-19,209, meloxicam, diclofenac, diflunisal, ibuprofen, and ketorolac. Rat dams were treated on gestation days (GDs) 9 and 10, and rabbit does were treated on GDs 9, 10, and 11. The doses selected for evaluation represented the maximum tolerable dose for the compound, with the exception of CJ-19,209, which was dosed at 1000 mg/kg. Fetuses were collected by cesarean section on GDs 21 and 29 for rats and rabbits, respectively, and all fetuses were examined for external and visceral developmental anomalies.

Results: In rabbits, diflunisal induced DH, VSD, and MD (omphalocele) and single incidences of VSD and MD (gastroschisis) were noted in the ibuprofen group; no other developmental findings were associated with treatment. In rats, ibuprofen, diflunisal, and ketorolac induced increases in the incidence of VSD. In general the induction of developmental defects was associated with compounds that selectively inhibit COX-1 or have a high ratio of COX-1 to COX-2 inhibition.

Conclusions: Inhibition of COX-1 may be involved in the disruption of heart development, whereas the selective inhibition of COX-2 (as assessed with CJ-19,209) appears to have no effect on heart development and midline closure in rats and rabbits.