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840. The evidence mounts up
TERATOGENESIS
545
only one agent is used alone.This may serve as a model for explaining some of the presently unaccounted for human malformations". 840. The evidence mounts up Landauer, W. & Clark, Ellen M. (1964). Teratogenic risks of drug synergism. Nature, Lond. 203, 527. A further cautionary note is sounded on the production of severe malformations from harmless amounts of potential teratogens when present in combination. Using the chick embryo technique, simultaneous injection of sulphanilamide (I) and 6-aminonicotinamide (II) both at non-toxic and non-teratogenic dose levels resulted in a large number of deaths and high incidence of malformations. The authors have postulated that I and II interfere with the same metabolic process on two grounds: first, that the abnormalities induced by the combined treatment of subteratogenic doses of I and II were similar in type to those produced by teratogenic doses of the two compounds administered separately; and second, that nicotinamide can afford protection against the teratogenic action of each compound. It was also suggested that I and II exercise their influence at different stages in the process since 2-deoxy-D-glucose accentuated the teratogenicity of II but had no effect on I. Whatever the mode of action, synergistic effects must be seriously considered as a contributory cause to the unexplained incidence of abnormalities, which occurs in all normapopulations. 841. Glutamine falls to reverse thalidomide embryopathy McColl, J. D., Globus, M. & Robinson, S. (1965). An attempted reversal of thalidomide embryopathy in the rat by glutamine. Can. J. Physiol. Pharmac. 43, 69. A further attempt has been made to elucidate the mechanism of teratogenic activity of thalidomide (I) in the rat. First of all the authors determined the normal incidence of hard and soft tissue abnormalities in 21-day-old foetuses of Sprague-Dawley rats which were given a dietary level of 2% I, commencing at 3 days before mating and continuing throughout gestation. Then attempts were made to alter this incidence by incorporating simultaneously into the diet/-glutamic acid or l-giutamine at levels of 2%. The incidence and type of gross defects, however, remained unaffected. The interpretation given was that neither of these essential growth factors is involved in the teratogenic activity of I. This work, if anything, should instil more confidence into those who believe that the phthaloyl grouping is the active factor in the embryopathy of I. 842. Salicylate teratogenicity: A biochemical basis Larsson, K. S. & Bostr6m, H. (1965). Teratogenic action of salicylates related to the inhibition of mucopolysaccharide synthesis. Acta paediat., Scand. 54, 43. Interference with acid mucopolysaccharide synthesis during the development of the mouse embryo has been implicated in the teratogenic action of cortisone (Larsson, Acta morph, neerl.-scand. 1962, 4, 369), and of another anti-inflammatory drug salicylic acid (Cited in F.C.T. 1964, 2, 87). The present authors, in an extension of their previous work, have attempted to correlate the potential teratogenic activity of three salicylate derivatives with their ability to inhibit acid mucopolysaccharide synthesis. The compounds chosen were the sodium salt of p-hydroxybenzoic acid, of salicylic acid and of its acetyl derivative. Intramuscular doses of 10 mg/compound were administered to pregnant mice on day 9 or 12 of gestation. Of the three compounds, only sodium salicylate exhibited teratogenic potential as evidenced by the considerably increased incidence of foetal resorptions and of vessel and
545
only one agent is used alone.This may serve as a model for explaining some of the presently unaccounted for human malformations". 840. The evidence mounts up Landauer, W. & Clark, Ellen M. (1964). Teratogenic risks of drug synergism. Nature, Lond. 203, 527. A further cautionary note is sounded on the production of severe malformations from harmless amounts of potential teratogens when present in combination. Using the chick embryo technique, simultaneous injection of sulphanilamide (I) and 6-aminonicotinamide (II) both at non-toxic and non-teratogenic dose levels resulted in a large number of deaths and high incidence of malformations. The authors have postulated that I and II interfere with the same metabolic process on two grounds: first, that the abnormalities induced by the combined treatment of subteratogenic doses of I and II were similar in type to those produced by teratogenic doses of the two compounds administered separately; and second, that nicotinamide can afford protection against the teratogenic action of each compound. It was also suggested that I and II exercise their influence at different stages in the process since 2-deoxy-D-glucose accentuated the teratogenicity of II but had no effect on I. Whatever the mode of action, synergistic effects must be seriously considered as a contributory cause to the unexplained incidence of abnormalities, which occurs in all normapopulations. 841. Glutamine falls to reverse thalidomide embryopathy McColl, J. D., Globus, M. & Robinson, S. (1965). An attempted reversal of thalidomide embryopathy in the rat by glutamine. Can. J. Physiol. Pharmac. 43, 69. A further attempt has been made to elucidate the mechanism of teratogenic activity of thalidomide (I) in the rat. First of all the authors determined the normal incidence of hard and soft tissue abnormalities in 21-day-old foetuses of Sprague-Dawley rats which were given a dietary level of 2% I, commencing at 3 days before mating and continuing throughout gestation. Then attempts were made to alter this incidence by incorporating simultaneously into the diet/-glutamic acid or l-giutamine at levels of 2%. The incidence and type of gross defects, however, remained unaffected. The interpretation given was that neither of these essential growth factors is involved in the teratogenic activity of I. This work, if anything, should instil more confidence into those who believe that the phthaloyl grouping is the active factor in the embryopathy of I. 842. Salicylate teratogenicity: A biochemical basis Larsson, K. S. & Bostr6m, H. (1965). Teratogenic action of salicylates related to the inhibition of mucopolysaccharide synthesis. Acta paediat., Scand. 54, 43. Interference with acid mucopolysaccharide synthesis during the development of the mouse embryo has been implicated in the teratogenic action of cortisone (Larsson, Acta morph, neerl.-scand. 1962, 4, 369), and of another anti-inflammatory drug salicylic acid (Cited in F.C.T. 1964, 2, 87). The present authors, in an extension of their previous work, have attempted to correlate the potential teratogenic activity of three salicylate derivatives with their ability to inhibit acid mucopolysaccharide synthesis. The compounds chosen were the sodium salt of p-hydroxybenzoic acid, of salicylic acid and of its acetyl derivative. Intramuscular doses of 10 mg/compound were administered to pregnant mice on day 9 or 12 of gestation. Of the three compounds, only sodium salicylate exhibited teratogenic potential as evidenced by the considerably increased incidence of foetal resorptions and of vessel and