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Title: Some biochemical aspects of thalidomide toxicity
Author: Hague, David Edward
Awarding Body: University of London
Current Institution: Imperial College London
Date of Award: 1969
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Abstract:
Chapter I reviews the thalidomide episode, and studies carried out on its embryotoxic properties. One of the puzzling features of thalidomide is that its teratogenic, neurotoxic and sedative properties are species dependent. Chapter II reviews the problem of species variations in response to foreign compounds. The effect of thalidomide in the hamster was studied following its administration to the pregnant animal. Unlike other species previously studied, the drug was found not to be teratogenic in the hamster. The fate of 14C -thalidomide following its administration to the pregnant hamster was investigated. The absorption and plasma levels of thalidomide, and the persistence and penetration of the teratogen in the embryo are described, and the results are compared to those found in the rabbit, a thalidomide sensitive species. No difference was observed, and it was concluded that the difference in teratogenicity must lie at the site of action of the compound. Chapters IV and V describe some physical and chemical properties of DL-thalidomide and its optical antipodes, and their acute toxicity in three strains of mice. The results show that the D- and L- isomers are toxic in both sexes of the three strains of mice whilst the racemate is not. A higher acute toxicity is also associated with the D- isomer. A comparison of DL-thalidomide and its antipodes indicate that this difference in toxicity is related to differences in their physico-chemical properties, for although those of the isomers were identical, they differed markedly from the racemate. For example, the solubilities, molecular weights and rates of hydrolysis were different. A comparison of the rates of excretion, plasma levels and tissue distribution of the three compounds was made following the administration to mice of 14C-labelled DL-, D- and L-thalidomide. The results are discussed. It was concluded that the racemate exists as a dimer in solution, and that its own toxicity may depend on its dissociation into the free isomers. Finally, in Chapter VII, the free amino acid pattern present in the rabbit embryo from the 6th to the 11th day of pregnancy is described, and the results compared to those found in the maternal plasma during this period. The effect thalidomide has on this pattern following its administration to the pregnant rabbit is also described. Seventeen amino acids were found in the blastocyst at 6 days. From the 6th to the 8th day, the general pattern of the amino acids altered quite radically, with large drops in the concentration of some amino acids, namely, threonine, serine, lysine, glycine, isoleucine, leucine and tyrosine, and arginine could no longer be detected. The changes which occur in the amino acid pattern, and the concentration ratios of the individual amino acids observed in the embryo, yolk sac and maternal plasma are discussed.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.518165  DOI: Not available
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