Arch Toxicol. 2003 Jan;77(1):7-11. Epub 2002 Oct 26. Related
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Children as a special population at risk--quinolones as an example
for xenobiotics exhibiting skeletal toxicity.

Stahlmann R.

Department of Toxicology, Institute of Clinical Pharmacology and
Toxicology, Benjamin Franklin Medical Center, Freie Universitat
Berlin, Garystrasse 5, 14195 Berlin, Germany.
ralf.stahlmann@m...

The sensitivity of the immature skeletal system during postnatal
mammalian development was discussed during the workshop "Children as
a Sensitive Subgroup and their Role in Regulatory Toxicology"
(Schwenk et al. 2002, Arch Toxicol, in press). As a typical example
of xenobiotics exhibiting this extraordinary type of toxicity, the
quinolone-induced effects on cartilage, bone growth, and tendons
were considered in depth. Animal experiments indicate that
chondrotoxicity of quinolones can affect articular cartilage
depending on the developmental stage. Results from studies with
pipemidic acid in dogs at various developmental stages from 1 week
old to 17 months old showed pronounced effects in the most sensitive
age groups: 3- to 6-month-old dogs exhibited gait alterations and
lameness, but signs of toxicity were not observed in 12- or 17-month-
old dogs. Similarly, experiments performed in rats indicate that
they exhibit the highest sensitivity for articular cartilage defects
at a certain stage of development between 3 and 6 weeks postnatally;
mature articular cartilage does not seem to be a target for
quinolone-induced toxicity. Some very limited data indicate that in
animals at an early developmental phase the epiphyseal growth plate
can also be damaged by quinolones, and that these effects are
associated with irreversible bone damage and growth inhibition.
Another manifestation of toxic effects of quinolones on connective
tissue structures are tendopathies. For this effect, it is not quite
clear whether juveniles are more susceptible than adults because
clinical and experimental data seem to point in different
directions. Pathogenesis of both effects can probably be explained
by the magnesium-chelating properties of these drugs, leading to a
deficit of functionally available magnesium and, subsequently, to
radical formation and irreversible connective tissue lesions.
However, unequivocal explanations for the phase-dependency of the
effects are lacking.

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