Lozo Edith, Riecke Kai, Schwabe Rudolf, Vormann Jürgen, Stahlmann Ralf
Institute of Clinical Pharmacology and Toxicology, Benjamin Franklin Medical Center, Freie Universität Berlin, 14195 Berlin, Germany.
Antimicrob Agents Chemother. 2002 Jun;46(6):1755-9. doi: 10.1128/AAC.46.6.1755-1759.2002.
Single high oral doses of fluoroquinolones (e.g., 1,200 mg of ofloxacin/kg of body weight) are chondrotoxic in juvenile rats. Characteristic cartilage lesions are detectable as early as 12 h after treatment. Since this dosing regimen does not reflect the therapeutic situation, we studied the effects of a 5- or 7-day treatment with ofloxacin at lower oral doses (10, 30, and 100 mg/kg twice a day [b.i.d.]) on joint cartilage in 4-week-old rats. We additionally investigated whether the effects of ofloxacin under these conditions are enhanced in animals kept on a magnesium-deficient diet during treatment. Knee joints were examined histologically. The concentrations of ofloxacin and magnesium were determined in plasma and cartilage. The lowest ofloxacin dose at which cartilage lesions occurred in animals on a standard diet was 100 mg/kg b.i.d. for 5 days. Peak plasma ofloxacin levels were approximately 10 mg/liter in these rats and thus were in the same range as the levels in the plasma of humans during therapy with high doses of ofloxacin. Treatment with 30 mg of ofloxacin/kg b.i.d. for 7 days caused no cartilage lesions in rats on a standard diet, but lesions did occur in 10 of 12 rats that were simultaneously fed a magnesium-deficient diet. Magnesium concentrations in bone, plasma, and cartilage from animals on an Mg(2+)-deficient diet were significantly lower than those in the controls. The concentration in plasma from animals on an Mg(2+)-deficient diet was 0.27 +/- 0.03 mmol/liter, whereas it was 0.88 +/- 0.08 mmol/liter in plasma from rats on a standard diet (means +/- standard deviations). Ofloxacin treatment did not change the total magnesium concentrations in tissues, as determined with ashed samples. The incidence of ofloxacin-induced lesions was higher in the magnesium-deficient animals, suggesting a synergistic effect. These results must be taken into account for a benefit-risk evaluation if ofloxacin is considered for use in the pediatric population.
单次口服高剂量氟喹诺酮类药物（如，1200毫克氧氟沙星/千克体重）对幼年大鼠具有软骨毒性。在治疗后12小时即可检测到特征性软骨损伤。由于这种给药方案不能反映治疗情况，我们研究了以较低口服剂量（10、30和100毫克/千克，每日两次[b.i.d.]）的氧氟沙星进行5天或7天治疗对4周龄大鼠关节软骨的影响。我们还研究了在治疗期间，饮食中缺镁的动物在这些条件下氧氟沙星的作用是否会增强。对膝关节进行组织学检查。测定血浆和软骨中氧氟沙星和镁的浓度。在标准饮食的动物中，出现软骨损伤的最低氧氟沙星剂量为每日两次100毫克/千克，持续5天。这些大鼠血浆中氧氟沙星的峰值水平约为10毫克/升，因此与高剂量氧氟沙星治疗期间人类血浆中的水平处于同一范围。以每日两次30毫克氧氟沙星/千克治疗7天，在标准饮食的大鼠中未引起软骨损伤，但在同时喂食缺镁饮食的12只大鼠中有10只出现了损伤。缺镁饮食动物的骨骼、血浆和软骨中的镁浓度显著低于对照组。缺镁饮食动物血浆中的浓度为0.27±0.03毫摩尔/升，而标准饮食大鼠血浆中的浓度为0.88±0.08毫摩尔/升（平均值±标准差）。用灰化样品测定，氧氟沙星治疗并未改变组织中的总镁浓度。缺镁动物中氧氟沙星诱导损伤的发生率更高，提示存在协同作用。如果考虑在儿科人群中使用氧氟沙星进行获益-风险评估时，必须考虑这些结果。
