Stahlmann R, Förster C, Shakibaei M, Vormann J, Günther T, Merker H J
Institut für Toxikologie und Embryopharmakologie, Freie Universität Berlin, Germany.
Antimicrob Agents Chemother. 1995 Sep;39(9):2013-8. doi: 10.1128/AAC.39.9.2013.
Quinolones accumulate in cartilage, and because they form chelate complexes with divalent cations, they possess the potential to induce a deficiency of functionally available magnesium. To test the hypothesis that quinolone-induced arthropathy is caused (or aggravated) by magnesium deficiency in cartilage, we induced magnesium deficiency by feeding juvenile rats a magnesium-deficient diet for 9 days and treated the rats with single oral doses of ofloxacin (0, 100, 300, 600, or 1,200 mg/kg of body weight) during this period. Additional groups of juvenile rats on a normal diet were treated with ofloxacin correspondingly. Typical cartilage lesions (e.g., swollen matrix, cleft formation) were found in knee joints of all magnesium-deficient rats, including those without ofloxacin treatment. Lesions in these groups were not distinguishable from lesions induced by a single dose of 600 mg of ofloxacin per kg of body weight or higher in rats on a normal diet. Ofloxacin levels in plasma after 600 mg/kg of body weight were approximately 10-fold higher than those in humans during therapy with this quinolone. Lesions in rats treated with ofloxacin plus magnesium deficiency were more pronounced than those in rats with normal magnesium concentrations. After intake of a magnesium-deficient diet for 9 days, the magnesium concentration in serum (mean +/- standard deviation) was 0.18 +/- 0.05 mmol/liter (control on normal diet, 0.82 +/- 0.10 mmol/liter). Magnesium concentrations in bone (femur) and cartilage (processus xiphoideus) samples were 64.7 +/- 10.5 and 14.3 +/- 3.9 mmol/kg of dry weight, respectively, which corresponded to approximately 50% of the concentrations measured in controls on a normal diet. It was concluded that quinolone-induced arthropathy is probably caused by a deficit of available magnesium in joint cartilage due to the formation of quinolone-magnesium chelate complexes. If juvenile patients must be treated with quinolones for serious infections, it seems prudent to ensure that these patients do not have a disturbed magnesium balance.
喹诺酮类药物在软骨中蓄积，并且由于它们能与二价阳离子形成螯合物，因此有可能导致功能性可用镁缺乏。为了验证喹诺酮类药物所致关节病是由软骨中镁缺乏引起（或加重）这一假说，我们通过给幼年大鼠喂食缺镁饮食9天来诱导其镁缺乏，并在此期间给大鼠单次口服不同剂量的氧氟沙星（0、100、300、600或1200mg/kg体重）。另外几组正常饮食的幼年大鼠也相应地接受氧氟沙星治疗。在所有缺镁大鼠的膝关节中都发现了典型的软骨损伤（如基质肿胀、裂隙形成），包括那些未接受氧氟沙星治疗的大鼠。这些组中的损伤与正常饮食大鼠单次给予600mg/kg体重或更高剂量氧氟沙星所致的损伤没有区别。给予600mg/kg体重氧氟沙星后大鼠血浆中的药物水平比人类使用该喹诺酮治疗期间的水平高约10倍。用氧氟沙星加镁缺乏处理的大鼠的损伤比镁浓度正常的大鼠更明显。在摄入缺镁饮食9天后，血清中的镁浓度（平均值±标准差）为0.18±0.05mmol/L（正常饮食对照组为0.82±0.10mmol/L）。骨骼（股骨）和软骨（剑突）样本中的镁浓度分别为64.7±10.5和14.3±3.9mmol/kg干重，分别约为正常饮食对照组测量浓度的50%。得出的结论是，喹诺酮类药物所致关节病可能是由于喹诺酮-镁螯合物的形成导致关节软骨中可用镁缺乏所致。如果必须用喹诺酮类药物治疗幼年患者的严重感染，确保这些患者的镁平衡未受干扰似乎是谨慎之举。
