Toxicity of bryostatin‐1 on the embryo‐fetal development of Sprague‐Dawley rats

BACKGROUND: Bryostatin‐1, a highly oxygenated marine macrolide with a unique polyacetate backbone isolated from the marine animal Bugula neritina (Linnaeus), is now being developed as an anti‐cancer drug for treating malignancy. In the present study, developmental toxicity of bryostatin‐1 was evaluated in Sprague–Dawley rats. METHODS: Bryostatin‐1 was intravenously administered to rats on gestation days 6–15 at 4.0, 8.0, and 16.0 µg/kg on a daily basis. Then the reproductive parameters were determined in animals, and fetuses were examined for external, visceral, and skeletal malformations. RESULTS: The total weight gains were significantly different in animals between the control group and 8.0 and 16.0 µg/kg bryostatin‐1 groups during and after treatment. The resorption and death fetus rates were significantly different between the bryostatin‐1 group (16 µg/kg) and the control group. The fetal weight and fetal crown‐rump length in the bryostatin‐1 groups were significantly lower than that in the control group. CONCLUSIONS: Our results indicated that maternal toxicity occurred when the dose of bryostatin‐1 was at 8.0 µg/kg, embryotoxicity at 16.0 µg/kg, and fetotoxicity at 4.0 µg/kg; but bryostatin‐1 showed no teratogenic effect in rats. In light of our findings, bryostatin‐1 should be used with caution in pregnant women with cancer, if they would like to continue the pregnancy. Birth Defects Res (Part B) 89:171–174, 2010. © 2010 Wiley‐Liss, Inc.     

Developmental toxicity evaluation of ibuprofen and tolmetin administered in triple daily doses to Wistar CRL:(WI)WUBR rats

BACKGROUND: Ibuprofen and tolmetin are popular non-steroidal anti-inflammatory drugs. Previous animal studies taken with single daily doses showed their good prenatal tolerability. However, since both cyclooxygenase (COX) inhibitors have a short half-life, the current report presents drug developmental effects after triple daily doses administration, as they are used in human. METHODS: Drugs were separately, orally dosed to pregnant rats triple daily 8 hr apart from day 8 to 21 (GD=1-plug day). The total daily doses were set at 25.5, 255.0, and 600.0 mg/kg for ibuprofen and 25.5, 255.0, and 2550.0 mg/kg for tolmetin. Fetuses were delivered on GD 21 and routinely examined. Comprehensive clinical and developmental measurements were done. RESULTS: Maternal toxicity and intrauterine growth retardation were found in groups exposed to the highest doses of both drugs. An increase of external variations was reported in groups exposed to the middle and highest dose of ibuprofen and to the highest dose of tolmetin. Skeletal variations were significantly different only in litters treated with the highest doses of the drugs. Pooled statistical analysis showed a higher incidence of midline and ventricular septal (VSD) defect in rat fetuses exposed to COX inhibitors when compared with historical control data. For ibuprofen, the influence on VSD was similar to aspirin. CONCLUSION: Both COX inhibitors were toxic to dams in the highest doses evaluated, which caused a significantly greater incidence of intrauterine growth retardation and developmental variations.     

Analysis of the nonsteroidal anti-inflammatory drug literature for potential developmental toxicity in rats and rabbits

BACKGROUND: Nonsteroidal anti‐inflammatory drugs (NSAIDs) are among the most commonly prescribed to pregnant women. Some case‐control studies have linked the NSAIDs aspirin and indomethacin with a risk of congenital abnormalities and low birthweight. High doses of aspirin produce developmental toxicity in rats (e.g., gastroschisis/umbilical hernia, diaphragmatic hernia [DH]) when administered during sensitive windows of development. Unlike other NSAIDs, aspirin irreversibly inhibits cyclooxygenases (COXs) 1 and 2. Hence, the developmental toxicity seen in rats after exposure to aspirin may be due to the irreversible inhibition of COX‐1 and/or COX‐2. If so, other NSAIDs, which act through a reversible inhibition of COX, may produce a weak developmental toxicity signal or no developmental toxicity signal when tested in preclinical models. To investigate this relationship, a comprehensive analysis of the NSAID developmental toxicity literature was undertaken to determine whether NSAIDs other than aspirin induce developmental anomalies similar to those elicited by aspirin. METHODS: Developmental toxicity studies were identified through literature searches of PubMed and TOXNET, and pregnancy outcome data were extracted and tabulated. By using a set of defined criteria, each study was evaluated for quality and assigned to one of five tiers. The relation between certain malformations and NSAID treatment was analyzed for the best studies (tiers 1–4) by using concurrent control data (Mantel–Haenszel and permutation tests) and by combining the concurrent control data with historical control data (χ² test and permutation tests). RESULTS: A qualitative analysis of these data led to a focus on three types of malformations: DH, ventricular septal defects (VSDs), and midline defects (MDs). In rats, the incidences of VSD and MD were increased among fetuses treated with NSAIDs when compared with the concurrent controls. The extent of the increase was attenuated when the data from the aspirin studies were excluded from the analysis. There were no qualifying (i.e., tiers 1–4) aspirin studies conducted in rabbits, but the incidences of the three defects were increased over control incidences among non‐aspirin NSAID‐treated animals. Statistical analysis of these data was subsequently conducted. When tiers 1–4 were combined and compared with concurrent controls plus the most appropriate historical control database, the strongest associations were between NSAID treatment and VSD in rats, VSD in rabbits, and MD in rabbits. There also was some suggestion of an association between NSAID treatment and DH in rabbits. CONCLUSIONS: This analysis of the non‐clinical NSAID literature demonstrated a possible association between exposure to NSAIDs and developmental anomalies. The anomalies were similar for aspirin and for other NSAIDs, but effects occurred at a much lower incidence with non‐aspirin NSAIDs than previously reported with aspirin. Such a finding is consistent with the concept that reversible inhibition of COX‐1 and/or COX‐2 by other NSAIDs would produce weaker developmental toxicity signals than aspirin. However, there were limitations of the evaluated studies: (1) there were very few robust International Conference on Harmonization–compliant studies conducted with NSAIDs in the published literature; (2) many of the studies were conducted at doses well below the maximum tolerated dose (MTD), where effects are rarely seen; and (3) numerous studies were conducted above the MTD, where reduced numbers of fetuses hampered detection of low‐incidence findings. Although weak associations were observed, these limitations prevented us from definitively determining the presence or absence of a developmental toxicity signal from the existing body of NSAID data. Further exploration of this hypothesis will require assessing the potential association in animal models by using dose levels centered around the MTD. Birth Defects Research (Part B) 68:5–26, 2003. © 2003 Wiley‐Liss, Inc.