Synergistic Effect of Ofloxacin and Magnesium Deficiency on Joint Cartilage in Immature Rats

Autor: Kai Riecke, E. Lozo, Ralf Stahlmann, Jürgen Vormann, Rudolf Schwabe
Rok vydání: 2002
Předmět:
Zdroj: Antimicrobial Agents and Chemotherapy. 46:1755-1759
ISSN: 1098-6596
0066-4804
DOI: 10.1128/aac.46.6.1755-1759.2002
Popis: Quinolones have the potential to cause joint cartilage damage in juvenile animals. Due to their arthropathogenic effects, the use of these antibacterials is contraindicated in children and adolescents. Clinical experience with some fluoroquinolones (e.g., ciprofloxacin), mainly in children with cystic fibrosis, has shown that no obvious acute toxicity occurs under these conditions; however, these findings cannot be generalized for other fluoroquinolones because major differences exist in pharmacokinetics and possibly also in toxicodynamics (16, 18; R. Stahlmann and H. Lode, Letter, Lancet 3352:1313, 1998). Investigations with immature animals and single high doses allow us to study the mechanism or other aspects of quinolone-induced chondrotoxicity, such as the latency period after dosing for such lesions to occur. Such an experimental setup, however, does not reflect the clinical situation (13). We now present data on a new experimental approach that corresponds to a standard clinical situation. Our studies were designed to answer the following questions: (i) is it possible to induce cartilage lesions in immature rats by treating them with multiple low, oral doses of ofloxacin (given twice a day [b.i.d.]) that lead to concentrations in plasma similar to those obtained in the plasma of humans during therapy with ofloxacin, and (ii) is there a synergistic effect on joint cartilage when the animals receive multiple, low (nonchondrotoxic) doses of ofloxacin and are simultaneously fed for a short period of time a magnesium-deficient diet which is not sufficient by itself to induce pronounced cartilage lesions? Background for the second part of the study were the findings that lesions resembling those observed after quinolone treatment can also be induced by feeding immature rats a magnesium-deficient diet for a period of 9 to 15 days (14, 19) and that supplementation with magnesium and/or tocopherol diminishes quinolone-induced arthropathy in immature rats (17). Furthermore, the effects of ofloxacin on Achilles tendons were more pronounced in rats on a magnesium-deficient diet than in rats on a standard diet (12). To provide a basis for an extrapolation of the results to humans, the concentrations of the quinolone were measured in the plasma and joint cartilage of juvenile rats on days 1 and 3 of treatment, as well as on day 6, i.e., 1 day after the last day of treatment of those rats that were studied histologically. To determine the effect of the diet on mineral concentrations in target organs, magnesium concentrations were measured in plasma, cartilage, and bone at the end of the treatment periods.
Databáze: OpenAIRE
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