Förster C, Schwabe R, Lozo E, Zippel U, Vormann J, Günther T, Merker H J, Stahlmann R
Institut für Klinische Pharmakologie und Toxikologie, Universitätsklinikum Benjamin Franklin, Freie Universität Berlin, Germany.
Arch Toxicol. 1997;72(1):26-32. doi: 10.1007/s002040050464.
Quinolone treatment or magnesium deficiency induce identical cartilage lesions in juvenile rats and show additive arthropathogenic effects. It has been shown previously that neither condition is arthropathogenic in 8-week-old rats. Joint cartilage from aged individuals is rather prone to pathological alterations but information on prolonged quinolone treatment and/or dietarily induced magnesium deficiency in aged animals is not available. We treated magnesium-deficient (n = 9) aged Wistar rats (age 15 months) and age-matched controls with daily doses of 600 mg ofloxacin/kg body wt. by gastric intubation for 28 days. Further groups of magnesium-deficient and control rats (n = 9 and n = 10, respectively) received the vehicle only. Peak plasma concentrations of ofloxacin in adult rats were 20.5 +/- 5.6 mg/l (mean +/- SD) following treatment with a single dose of 600 mg/kg body wt. At the end of the experiment the degree of magnesium deficiency was most pronounced in plasma (Mg2+-def., 0.33 +/- 0.12 mmol/l; control, 0.97 +/- 0.08 mmol/l) and less pronounced in sternal cartilage (Mg2+-def., 10.8 +/- 3.6 mmol/kg dry wt; control, 13.3 +/- 2.8 mmol/kg dry wt), whereas the magnesium concentration in femoral bone remained unchanged (Mg2+-def., 201 +/- 13 mmol/kg dry wt; control, 204 +/- 11 mmol/kg dry wt). Histological investigation of the knee joints revealed no cartilage lesions following ofloxacin treatment, magnesium deficiency or a combination of both conditions. By contrast, cartilage lesions such as scars and erosions of the joint surface, chondrocyte clusters within acellular areas of the cartilage matrix and persisting clefts were detectable in knee joints from 7 of 10 adult rats (age 9 months) which had been treated with 4 x 600 mg fleroxacin/kg body wt. at 5 weeks of age. Mean plasma concentration of fleroxacin in juvenile rats was approx. 50 mg/l between 1.5 and 6 h after dosing and the drug was still detectable in plasma 48 h after dosing (0.4 +/- 0.1 mg/l). Our data indicate that joint cartilage in aged rats is not altered by a 4-week quinolone treatment, even during magnesium deficiency. Cartilage lesions in adult rats were only detectable if the animals had been treated during the sensitive phase at 5 weeks postnatally.
喹诺酮治疗或镁缺乏在幼年大鼠中会引发相同的软骨损伤，并显示出叠加的致关节病作用。此前已表明，这两种情况在8周龄大鼠中均不会引发关节病。老年个体的关节软骨更容易发生病理改变，但关于老年动物长期喹诺酮治疗和/或饮食诱导的镁缺乏的信息尚不可得。我们对缺镁的（n = 9）15月龄老年Wistar大鼠和年龄匹配的对照大鼠进行胃内插管，每日给予600 mg氧氟沙星/ kg体重，持续28天。另外几组缺镁和对照大鼠（分别为n = 9和n = 10）仅接受赋形剂。成年大鼠单次给予600 mg/kg体重治疗后，氧氟沙星的血浆峰值浓度为20.5±5.6 mg/l（平均值±标准差）。实验结束时，血浆中的镁缺乏程度最为明显（缺镁组，0.33±0.12 mmol/l；对照组，0.97±0.08 mmol/l），胸骨软骨中的程度较轻（缺镁组，10.8±3.6 mmol/kg干重；对照组，13.3±2.8 mmol/kg干重），而股骨中的镁浓度保持不变（缺镁组，201±13 mmol/kg干重；对照组，204±11 mmol/kg干重）。膝关节的组织学检查显示，氧氟沙星治疗、镁缺乏或两种情况联合处理后均未发现软骨损伤。相比之下，在10只9月龄成年大鼠中，有7只在5周龄时接受4×600 mg氟罗沙星/kg体重治疗，其膝关节中可检测到软骨损伤，如关节表面的瘢痕和侵蚀、软骨基质无细胞区域内的软骨细胞簇以及持续的裂隙。幼年大鼠给药后1.5至6小时内，氟罗沙星的平均血浆浓度约为50 mg/l，给药后48小时血浆中仍可检测到该药物（0.4±0.1 mg/l）。我们的数据表明，即使在镁缺乏期间，老年大鼠的关节软骨也不会因4周的喹诺酮治疗而改变。成年大鼠只有在出生后5周的敏感阶段接受治疗，才会检测到软骨损伤。
