CORRELATION OF TERATOGENICITY OF ASPIRIN TO THE STAGESPECIFIC DISTRIBUTION OF SALICYLIC ACID IN RATS
A study was made of the stage-specific teratogenicity in rat fetuses from dams given different dosages of aspirin throughout and also during 3 subdivided organogenetic periods of pregnancy (days 8-10, 11-13 and 15-17 of gestation). The stage-specific teratogenicity of the drug, from the aspect of th...
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Published in | Japanese journal of pharmacology Vol. 31; no. 4; pp. 563 - 571 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
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The Japanese Pharmacological Society
1981
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Abstract | A study was made of the stage-specific teratogenicity in rat fetuses from dams given different dosages of aspirin throughout and also during 3 subdivided organogenetic periods of pregnancy (days 8-10, 11-13 and 15-17 of gestation). The stage-specific teratogenicity of the drug, from the aspect of the dam-fetus distribution pattern of salicylic acid during the respective periods of pregnancy was also determined. The stage when the malformations, typical of aspirin toxicity (cranioschisis, spondyloschisis, abdominal fissure, cleft palate) were most frequent was from day 8 to day 10 of gestation. Even in this period when the fetuses were most susceptible to this teratogen, however, the drug was not teratogenic unless it was ingested for 3 or more consecutive days. There were no significant alterations in the maternal plasma levels of salicylic acid during the respective periods. During the first 8-10 days of gestation, the fetal levels of salicylic acid remained significantly high (p<0.05) at any stage of measurement during the 10 hours after application of aspirin, compared with the maternal plasma levels. Furthermore, as pregnancy progressed, the amount of salicylic acid transferred to the fetuses tended to gradually decrease, despite of the fact that the maternal plasma levels of the agent remained fairly stable. On the other hand, the placental levels of salicylic acid tended to be increasingly elevated with the pregression of pregnancy. Thus, salicylic acid is most readily transferred to the fetuses at high concentrations at days 8-10 of gestation. Also, from the finding that aspirin proved to be teratogenic when the fetuses were exposed to a given period (3 days or more), the teratogenic action of aspirin is attributed to a direct action of this compound. |
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AbstractList | A study was made of the stage-specific teratogenicity in rat fetuses from dams given different dosages of aspirin throughout and also during 3 subdivided organogenetic periods of pregnancy (days 8-10, 11-13 and 15-17 of gestation). The stage-specific teratogenicity of the drug, from the aspect of the dam-fetus distribution pattern of salicylic acid during the respective periods of pregnancy was also determined. The stage when the malformations, typical of aspirin toxicity (cranioschisis, spondyloschisis, abdominal fissure, cleft palate) were most frequent was from day 8 to day 10 of gestation. Even in this period when the fetuses were most susceptible to this teratogen, however, the drug was not teratogenic unless it was ingested for 3 or more consecutive days. There were no significant alterations in the maternal plasma levels of salicylic acid during the respective periods. During the first 8-10 days of gestation, the fetal levels of salicylic acid remained significantly high (p<0.05) at any stage of measurement during the 10 hours after application of aspirin, compared with the maternal plasma levels. Furthermore, as pregnancy progressed, the amount of salicylic acid transferred to the fetuses tended to gradually decrease, despite of the fact that the maternal plasma levels of the agent remained fairly stable. On the other hand, the placental levels of salicylic acid tended to be increasingly elevated with the pregression of pregnancy. Thus, salicylic acid is most readily transferred to the fetuses at high concentrations at days 8-10 of gestation. Also, from the finding that aspirin proved to be teratogenic when the fetuses were exposed to a given period (3 days or more), the teratogenic action of aspirin is attributed to a direct action of this compound. |
Author | TAGASHIRA, Eijiro HIRAMORI, Tameo URANO, Tomoko YANAURA, Saizo NAKAO, Kenzo ISHIKAWA, Shigeru |
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References | 11) Obbink, H.J.K. and Dalderup, L.M.: Effect of acetylsalicylic acid on foetal mice and rats. Lancet I, 565 (1964 3) Nagahama, M., Akiyama, N. and Miki, T.: Experimental production of malformations due to salicylates (acetyl salicylate and phenyl salicylate) in rats. Cong. Anom. 6, 20-27 (1966 7) Koshakji, R.P. and Schulert, A.P.: Biochemical mechanisms of salicylate teratology in the rat. Biochem. Pharmacol. 22, 407-416 (1973 15) Shapiro, S., Siskind, V., Monson, R.R., Heinonen, O.P., Kaufman, D.W. and Slone, D.: Perinatal mortality and birthweight in relation to aspirin taken during pregnancy. Lancet I, 1375-1376 (1976 17) Wilson, J.G.: Use of rhesus monkeys in teratological studies. Fedn. Proc. 30, 104-109 (1971 1) Warkany, J. and Takacs, E.: Experimental production of congenital malformations in rats by salicylate poisoning. Am. J. Pathol. 35, 315-330 (1959 9) Miyamoto, T. and Nagahama, M.: Experimental studies of congenital hydrops induced by acetyl salicylate (aspirin) in rats. Cong. Anom. 7, 167 (1967 13) Turner, G. and Collins, E.: Fetal effects of regular salicylate ingestion in pregnancy. Lancet II, 338-339 (1975 18) Beck, F., Lloyd, J.B. and Griffiths, A.: Lysosomal enzyme inhibition by trypan blue: A theory of teratogenesis. Science 157, 1180-1182 (1967 12) Collins, E. and Turner, G.: Maternal effects of regular salicylate ingestion in pregnancy. Lancet II, 335-337 (1975 4) Tanaka, S., Kawashima, K., Nakaura, S., Nagao, S., Kuwamura, T., Takanaka, A. and Omori, Y.: Studies on teratogenic effects of salicylic acid and aspirin in rats as related to fetal distribution. Cong. Anom. 13, 73-84 (1973 14) Slone, D., Siskind, V., Heinonen, O.P., Monson, R.R., Kaufman, D.W. and Shapiro, S.: Aspirin and congenital malformations. Lancet I, 1373-1375 (1976 16) Collins, E. and Turner, G.: Aspirin during pregnancy. Lancet II, 797-798 (1976 2) Nagahama, M., Akiyama, N. and Miki, T.: Experimental production of malformations due salicylates (acetyl salicylate and phenyl salicylate) in rats. Cong. Anom. 5, 236-237 (1965 8) Akiyama, N. and Nagahama, M.: Embryological studies on the congenital skeletal anomalies induced by acetyl salicylate (aspirin) in rats. Cong. Anom. 6, 171 (1966 10) Goldman, A.S. and Yakovac, W.C.: Salicylate intoxication and congenital anomalies. Arch. Environmt. Health 8, 648-656 (1964 5) Blattner, R.J.: Teratogenic action of salicylate in mice: Effect on mucopoly saccharide synthesis. J. Pediat. 66, 1102-1104 (1965 6) Kimmel, C.A., Wilson, J.G. and Schumacher, H.T.: Studies on metabolism and identification of the causative agent in aspirin teratogenesis in rats. Teratology 4, 15-24 (1971 |
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