Possible Relationship Between Tetracycline Stability and Effect on Foetal Skeleton

Abstract

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.

The Use of Clomocycline (‘Megaclor‘) in Acute Respiratory Infections

“…In view of the findings that the less stable tetracyclines are not taken up so readily in the foetal skeleton (Tubaro 1964b), and the report (Owens & Stewart 1967) that Clomocycline in daylight stained the teeth of children less than other tetracyclines, it would also appear that when tetracyclines are indicated in acute respiratory infections in children, Clomocycline would be the drug of choice.…”