The effect of tetracycline on the development of the skeletal system of the chick embryo

Bevelander, Gerrit; Nakahara, Hiroyuki; Rolle, Gloria K.

doi:10.1016/0012-1606(60)90011-7

Cited by 62 publications

(9 citation statements)

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“…Several in vitro studies (Kaitila 1971, West & Storey 1972 have indicated that tetracyclines exert their main effect on bone by inhibiting the calcification. In vivo studies, however, have provided confusing results (Bevelander et al 1960, Ogawa et al 1961, Harris et al 1968.…”

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confidence: 99%

Effects of Oxytetracycline on Mineralization of Bone in Young Rats

Engesæter

Underdal

Langeland

1980

Acta Orthopaedica Scandinavica

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The metabolism of minerals and collagen in young rats receiving oxytetracycline was studied by employing double-isotope techniques. The dosage of the antibiotic was adjusted to obtain plasma concentrations comparable with human therapeutic levels. Reduced mineralization and possibly increased resorption of bone were observed after oxytetracycline administration, whereas no effect on the rate of collagen synthesis could be detected.

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confidence: 99%

Effects of Oxytetracycline on Mineralization of Bone in Young Rats

Engesæter

Underdal

Langeland

1980

Acta Orthopaedica Scandinavica

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“…There appears to -be direct relationship between the stability of a tetracycline and its concentration in the foetal skeleton as demonstrated by fluorescence; this is probably related to a longer persistence in the foetal blood of more stable tetracyclines during the time of bone formation. Although it was not possible to find true malformations in our experiments with rabbits and rats, there is ample evidence in the literature on the influence of tetracyclines in delaying growth and causing malformations (Filippi & Mela, 1957;Bevelander, Goldberg & Nakahara, 1960;Bevelander, Nakahara & Rolle, 1960;Carter & Wilson, 1962;Cohlan, Bevelander & Bross, 1962;Cohlan, Bevelander & Tiamsic, 1963).…”

Section: Discussionmentioning

confidence: 76%

Possible Relationship Between Tetracycline Stability and Effect on Foetal Skeleton

Tubaro¹

1964

British Journal of Pharmacology and Chemotherapy

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A possible relationship between stability of a tetracycline and persistence in the foetal skeleton is discussed; it seems that the greater the stability of a tetracycline, the more it may interfere with bone-forming processes. Therefore, assuming that limited instability does not impair antibiotic potency in vivo, the use of a low-stability tetracycline seems to be a safer form of treatment in order to avoid undesired effects on the foetal skeleton.In recent years the occurrence of skeletal malformations in animal and human foetuses after administration of tetracycline has frequently been reported (Bevelander, Nakahara & Rolle, 1959;Bevelander & Goss, 1962;Wallman & Hilton, 1962;Hurley & Tuchmann-Duplessis, 1963.;Smith & Chapman, 1963); this occurrence is probably due to the typical avidity of tetracycline for metal cations acting as a prosthetic group in bone-forming enzymes (Eagle & Saz, 1955; Shils, 1962).All the investigations on teratogenicity or abnormal bone calcifications have until now been carried out with tetracycline itself and not with other members of this group; moreover, in the case of tetracycline, only the relationship between abnormal effect and dosage or length of treatment has been investigated. In the course of work on the monosodium salt of N-methylol-chlortetracycline (chlormethylenecycline), experiments on developing chick embryos were carried out with the object of evaluating possible variations of its chelating effect compared with the actions of other tetracyclines. METHODSChick embryos of an inbred hybrid strain were used 8 days after the onset of hatching; single 1 mg doses of demethylchlortetracycline, tetracycline, chlortetracycline and the monosodium salt of chlormethylenecycline were dissolved in 0.1 ml. and were injected under sterile conditions into the yolk sac of the embryo. Demethylchlortetracycline, tetracycline and chlortetracycline were used as the hydrochlorides. All doses refer to the bases.Eggs were sealed with sterile cellulose tape and placed in an incubator at 38 C; embryos and their sagittal sections (prepared by the same method as for rabbits; see below) were examined on the 16th day after the onset of hatching and were viewed under ultra-violet light.Groups of five female rabbits were injected intravenously from the 10th to 20th day of pregnancy with 10 mg/kg/day of the tetracyclines. The neonates were then rapidly frozen with a dry-ice mixture of solid carbon dioxide and acetone and whole-body sagittal sections were cut using a 1213 Leitz freezing microtome equipped with a 90 mm Jung type C knife.

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“…It is unlikely that the effects are specific to the chick since the tetracyclines were all deposited in the immature bones and also a wide range of embryos have previously been used (Bevelander, Nakahara and Rolle, 1960;Bevelander, Goldberg and Nakahara, 1960) including fish (Bevelander & Goss, 1962), mice (Fillipi & Mala, 1958), chicks (Tchernoukh & Alexandrov, 1963) and puppies (Owen, 1963).…”

Section: Discussionmentioning

confidence: 99%

A Comparative Study of the Actions of Six Tetracyclines on the Development of the Chick Embryo

Hughes

Lee

Flood

1965

British Journal of Pharmacology and Chemotherapy

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The series of studies of Bevelander and his colleagues, conveniently summarized in his letter (1963), together with the observations collected by Shils (1962), has focused attention on the potentially toxic nature of the tetracyclines particularly in embryos and in developing tissues. It was felt that a comparison should be made between older and newer, more soluble tetracyclines to try to discover whether alteration in the molecule had increased toxicity and whether any teratogenic effects could be detected. METHODSThe design of the first experiment was based as closely as possible on the blind trial. Solutions of tetracycline, oxytetracycline, chlortetracycline, demethylchlortetracycline, lemecycline and chlormethylencycline were made up in Dulbecco's phosphate-buffered saline (Oxoid), pH 7.3, the buffer itself being introduced as one control, a second being provided by the remainder of the batch which was not injected or manipulated in any way. The concentrations used were those commonly found in the blood during therapy, about 2.5 /Ag/ml. (125 ug contained in 0.2 ml. of buffer for each 50 g of egg). As the concentration in cord blood is half that in the mother, even this level would be higher than that to which an infant would be exposed (Charles, 1954; Gibbons & Richelderfer, 1960). We have ourselves tested paired maternal and cord bloods and have obtained concordant results.A hatchery made available a batch of eggs from chickens with high fertility. On the 4th day of incubation these were candled and infertile eggs were discarded. Twenty eggs were placed in each group, the injection site marked, waxed and perforated. Volumes of 0.2 ml. of the drug were injected and the shells were resealed by melting the wax. Injections were made into the allantoic cavity through the corion.In a second series using ten-times the previous level of drug, the tetracyclines were prepared as before, but more stringent sterility tests of the solutions were made. The drugs were dissolved and diluted for use within 2 hr of being injected to avoid as far as possible any loss of potency while in solution. They were not however refrigerated during transportation.The concentrations of the drugs were on a simple weight basis and allowances were not made for differences in molecular weights.The assessment of the health of the chicks was made by the hatchery. The nature of the drugs administered was not known, the groups being identified only by batch letter. Chicks killed by gassing and unhatched eggs were then forwarded for further work. The unhatched embryos were dissected and examined for any abnormality. Representative bones were selected for histology after examination for fluorescence. These were compared with those of the survivors from the respective

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The effect of tetracycline on the development of the skeletal system of the chick embryo

Cited by 62 publications

References 9 publications

Effects of Oxytetracycline on Mineralization of Bone in Young Rats

Effects of Oxytetracycline on Mineralization of Bone in Young Rats

Possible Relationship Between Tetracycline Stability and Effect on Foetal Skeleton

A Comparative Study of the Actions of Six Tetracyclines on the Development of the Chick Embryo

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