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847. Reaction of tetracycline with metals and proteins
652
PRESERVATIVES
ized by glucosuria, phosphaturia, aminoaciduria and acidosis with or without proteinuria and rickets (Cited in F.C.T. 1963, 1, 259). Cleveland et aL (cited above) now report 3 similar cases in 1 adult and 2 children. In addition to the signs listed above, the children showed marked potassium (K) depletion and a low blood level of K with consequent serious clinical manifestations which required large amounts of K salts for their correction. The aminoaciduria persisted after all the other signs had subsided; and striking differences were found in the time taken for the excretion of 24 separate amino acids to return to normal. The ability of outdated I to induce the Fanconi syndrome is due to toxic degradation products. Old capsules of I have been found to contain twice as much anhydro-I (II) as remaining I, and also small amounts of anhydro-4-epi-I (II:I) (Frimpter et al. J. Am. reed. Ass. 1963, 184, 111). 4-Epi-I (IV) is another breakdown product of I. Formation of II, III and IV is promoted by heat, moisture and decreased pH. The toxicity of I, II, Ill and IV has been studied in rats (single oral doses of I g/kg) and dogs (intravenoug doses of 10-20 mg/kg) by Benitz & Diermeier (cited above). Only III produced kidney damage; tubular necrosis was found in all 6 rats and in the sole dog given III. A lower dose of IV (275 mg/kg) even in combination with I, II and III (total dose 500 mg/kg) proved ineffective in rats. The rats also showed proteinuria, glucosuria and increased urinary excretion of glutamie-oxaloaeetie transaminase. It is thus possible that III may be the toxic principle in outdated I that is responsible for the production of the Fanconi syndrome. 847. Reaction of tetracycline with metals and proteins G~ibert, H. (1965). Fermentinaktivierungen durch Tetracycline. Arch. exp. Path. Pharmak. 250, 72. Tetracycline (I) is known to accumulate in bones, teeth and tumours after prolonged ingestion. LocaliTation in skeletal tissues may be related to the ability of I to form complexes with metal ions; and in tumours to the formation of complexes with peptides (British Medical Journal ) 1962, 1, 1401). Formation of metal complexes may also be involved in protein-I interactions since I has been found to bind in vitro with serum proteins and also with pure albumin and T-globulin on addition of zinc, magnesium, aluminium and iron salts. The activities of several metalcontaining or metal-dependent enzymes, namely peroxidase, and serum and leucocyte alkaline phosphatases, were found to be inhibited in vitro by I although catalase activity was unaffected. In view of the relatively high concentrations of I necessary to inhibit enzyme activities in vitro, it seems doubtful whether effective concentrations would be reached in vivo except perhaps in the kidneys, skeletal tissues and tumours, where I accumulates on prolonged administration. The practical clinical significance of these observations, if any, remains to be determined. 848. Effect on nitrate and nitrite on carotene absorption
Mitchell, G. E., Little, C. O., Jr. & Greathouse, T. R. (1964). Influence of nitrate and nitrite, on carotene disappearance from the rat intestine. Life Sci. 4, 385. Ingestion of nitrate (I) and nitrite (II) can cause a decreased storage of vitamin A in the liver of cattle, sheep and rats and sometimes can produce signs of vitamin A deficiency. Reduced hepatic storage of vitamin A has been attributed to faulty conversion of carotene to vitamin A in which hypothyroidism may be a contributory factor (Cited in F.C.T. 1963 1, 277 & 278). Since the intestine is the primary and probably the major site of this conversion, the effect of dietary I and II on the rate of disappearance of carotene from the small intestine of the rat has now been studied.
PRESERVATIVES
ized by glucosuria, phosphaturia, aminoaciduria and acidosis with or without proteinuria and rickets (Cited in F.C.T. 1963, 1, 259). Cleveland et aL (cited above) now report 3 similar cases in 1 adult and 2 children. In addition to the signs listed above, the children showed marked potassium (K) depletion and a low blood level of K with consequent serious clinical manifestations which required large amounts of K salts for their correction. The aminoaciduria persisted after all the other signs had subsided; and striking differences were found in the time taken for the excretion of 24 separate amino acids to return to normal. The ability of outdated I to induce the Fanconi syndrome is due to toxic degradation products. Old capsules of I have been found to contain twice as much anhydro-I (II) as remaining I, and also small amounts of anhydro-4-epi-I (II:I) (Frimpter et al. J. Am. reed. Ass. 1963, 184, 111). 4-Epi-I (IV) is another breakdown product of I. Formation of II, III and IV is promoted by heat, moisture and decreased pH. The toxicity of I, II, Ill and IV has been studied in rats (single oral doses of I g/kg) and dogs (intravenoug doses of 10-20 mg/kg) by Benitz & Diermeier (cited above). Only III produced kidney damage; tubular necrosis was found in all 6 rats and in the sole dog given III. A lower dose of IV (275 mg/kg) even in combination with I, II and III (total dose 500 mg/kg) proved ineffective in rats. The rats also showed proteinuria, glucosuria and increased urinary excretion of glutamie-oxaloaeetie transaminase. It is thus possible that III may be the toxic principle in outdated I that is responsible for the production of the Fanconi syndrome. 847. Reaction of tetracycline with metals and proteins G~ibert, H. (1965). Fermentinaktivierungen durch Tetracycline. Arch. exp. Path. Pharmak. 250, 72. Tetracycline (I) is known to accumulate in bones, teeth and tumours after prolonged ingestion. LocaliTation in skeletal tissues may be related to the ability of I to form complexes with metal ions; and in tumours to the formation of complexes with peptides (British Medical Journal ) 1962, 1, 1401). Formation of metal complexes may also be involved in protein-I interactions since I has been found to bind in vitro with serum proteins and also with pure albumin and T-globulin on addition of zinc, magnesium, aluminium and iron salts. The activities of several metalcontaining or metal-dependent enzymes, namely peroxidase, and serum and leucocyte alkaline phosphatases, were found to be inhibited in vitro by I although catalase activity was unaffected. In view of the relatively high concentrations of I necessary to inhibit enzyme activities in vitro, it seems doubtful whether effective concentrations would be reached in vivo except perhaps in the kidneys, skeletal tissues and tumours, where I accumulates on prolonged administration. The practical clinical significance of these observations, if any, remains to be determined. 848. Effect on nitrate and nitrite on carotene absorption
Mitchell, G. E., Little, C. O., Jr. & Greathouse, T. R. (1964). Influence of nitrate and nitrite, on carotene disappearance from the rat intestine. Life Sci. 4, 385. Ingestion of nitrate (I) and nitrite (II) can cause a decreased storage of vitamin A in the liver of cattle, sheep and rats and sometimes can produce signs of vitamin A deficiency. Reduced hepatic storage of vitamin A has been attributed to faulty conversion of carotene to vitamin A in which hypothyroidism may be a contributory factor (Cited in F.C.T. 1963 1, 277 & 278). Since the intestine is the primary and probably the major site of this conversion, the effect of dietary I and II on the rate of disappearance of carotene from the small intestine of the rat has now been studied.