Comparison of the developmental toxicity of aspirin in rabbits when administered throughout organogenesis or during sensitive windows of development

Cappon, Gregg D.; Gupta, U; Cook, Jon C.; Tassinari, Melissa S.; Hurtt, Mark E.

doi:10.1002/bdrb.10004

Cited by 22 publications

(17 citation statements)

References 20 publications

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“…Interestingly, the fetal weight of the fetuses prenatally exposed to COX inhibitors was significantly higher when compared with the untreated control group. However, the intrauterine growth retardation observed in rat fetuses with MD has been previously reported also in rabbits (18). Such findings were confirmed for other congenital anomalies, including diaphragmatic hernia, which, similar to VSDs and MDs, has been related to prenatal exposure to COX inhibitors (17)(18)(19).…”

Section: Discussionsupporting

confidence: 70%

“…However, the intrauterine growth retardation observed in rat fetuses with MD has been previously reported also in rabbits (18). Such findings were confirmed for other congenital anomalies, including diaphragmatic hernia, which, similar to VSDs and MDs, has been related to prenatal exposure to COX inhibitors (17)(18)(19). It is worth mentioning that the incidence of MDs in the rat group exposed to aspirin was significantly higher when compared to other nonselective COX inhibitors (P = 0.019), ibuprofen itself (P = 0.005), and selective COX-2 inhibitors (P < 0.0001) (16).…”

Section: Discussionmentioning

confidence: 78%

“…Aspirin, unlike other common NSAIDs, is an irreversible COX inhibitor which at low doses selectively blocks the COX-1 isoenzyme (18,23). This mechanism also explains the good prenatal tolerance of COX-2 selective compounds, which induce only intrauterine growth retardation when administered at high doses.…”

Section: Discussionmentioning

confidence: 99%

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Congenital ventricular septal defects and prenatal exposure to cyclooxygenase inhibitors

Burdan

Szumiło

Dudka

et al. 2006

Braz J Med Biol Res

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Ventricular septal defects (VSDs) are common congenital abnormalities which have been reported to be associated with maternal fever and various environmental factors. The aim of the present study was to evaluate the effect of prenatal exposure to cyclooxygenase (COX) inhibitors on heart defects. A retrospective statistical analysis was performed using data collected in our laboratory during various teratological studies carried out on albino CRL:(WI)WUBR Wistar strain rats from 1997 to 2004. The observations were compared with concurrent and historic control data, as well as findings from other developmental toxicological studies with selective and nonselective COX-2 inhibitors. Despite the lack of significant differences in the frequency of VSDs between drug-exposed and control groups, statistical analysis by the two-sided Mantel-Haenszel test and historical control data showed a higher incidence of heart defects in offspring exposed to nonselective COX inhibitors (30.06/10,000). Unlike other specific inhibitors, aspirin (46.26/10,000) and ibuprofen (106.95/ 10,000) significantly increased the incidence of the VSD when compared with various control groups (5. 38-19.72/10,000). No significant differences in length or weight were detected between fetuses exposed to COX inhibitors and born with VSD and non-malformed offsprings. However, a statistically significant increase of fetal body length and decrease of body mass index were found in fetuses exposed to COX inhibitors when compared with untreated control. We conclude that prenatal exposure to COX inhibitors, especially aspirin and ibuprofen, increased the incidence of VSDs in rat offspring but was not related to fetal growth retardation.

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Section: Discussionsupporting

confidence: 70%

Section: Discussionmentioning

confidence: 78%

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Congenital ventricular septal defects and prenatal exposure to cyclooxygenase inhibitors

Burdan

Szumiło

Dudka

et al. 2006

Braz J Med Biol Res

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“…Hence, studies conducted well below the MTD and those conducted with doses exceeding the MTD may be unable to detect low-incidence developmentally toxic effects of NSAIDs. The potential association of NSAIDs with developmental toxicity, as shown by the literature, and the limitations of this data set, as discussed above, led to us to reinvestigate the developmental toxicity of aspirin in rats and rabbits in a series of studies by using two different dosing paradigms (Cappon et al, 2003b;Gupta et al, 2003), to assess the developmental toxicity of NSAIDs with different COX-1 and COX-2 specificities (Cappon et al, 2003a), and to examine the expression of COX-1 and COX-2 in developing rat embryos (Streck et al, 2003). Concurrent with these studies, a metaanalysis of the human epidemiologic data was conducted examining the use of aspirin during pregnancy by analyzing first-trimester outcomes (Kozer et al, 2002) and second-and third-trimester outcomes (Kozer et al, 2003).…”

Section: Mousementioning

confidence: 99%

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

Cook¹,

Jacobson²,

Gao³

et al. 2003

Birth Defects Research Pt B

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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.

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“…Knowledge of adverse drug-induced oral effects helps health professionals to better diagnose oral disease, administer drugs and improve patient compliance (Femiano et al, 2008). Cappon and co-workers, in their study, did not find any teratogenic effect of Aspirin in rabbits even when large doses were administered on single day during specific windows of development (Cappon et al, 2003) however, teratogenicity of aspirin has been reported at high doses in rodents (Berry & Nickols, 1979). There is scarcity of literature regarding the effect of aspirin on minerals in the dental tissues.…”

Section: Introductionmentioning

confidence: 94%

Effect of Aspirin on the Developing Teeth of Neonates

et al. 2011

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SUMMARY:The objective of the present study was to evaluate the effect of aspirin (Acetyl Salicylic Acid) on the developing teeth of the fetus while the mothers were treated through out the pregnancy. Aspirin is a widely used analgesic and antipyretic drug used for symptomatic treatment. However, recent animal studies have indicated a potent teratogenicity of Acetyl Salicylic Acid. Its easy availability without prescription has been associated with high possibility of misuse, especially in the developing world. An experimental control study was carried out where female rabbits being treated with aspirin were taken as mammalian model, and their offspring were used to evaluate the developmental defects in teeth. Quantitative analysis of minerals in three types of the sample teeth, was done using scanning electron microscope and energy dispersive X-ray spectroscopy (SEM-EDX). Calcium was the most affected mineral and incisors and mandibular molars were found to be the most affected teeth. Voluminous variations were observed in the mineral contents of samples from the treated and control group, however, significant results could not be achieved. A larger sample size could possibly be needed to produce more conclusive results.

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Comparison of the developmental toxicity of aspirin in rabbits when administered throughout organogenesis or during sensitive windows of development

Abstract: These findings supported previous work demonstrating that ASA is not teratogenic in rabbits, as opposed to rats, even when large doses are administered on single days during specific windows of development.

Cited by 22 publications

References 20 publications

Congenital ventricular septal defects and prenatal exposure to cyclooxygenase inhibitors

Congenital ventricular septal defects and prenatal exposure to cyclooxygenase inhibitors

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

Effect of Aspirin on the Developing Teeth of Neonates

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