Magnesium deficiency induces joint cartilage lesions in juvenile rats which are identical to quinolone-induced arthropathy

ABSTRACT Sparfloxacin is a fluoroquinolone with improved antibacterial activity against gram-positive pathogens. Like other quinolones, use of this drug is contraindicated in children and adolescents because of its potential chondrotoxicity in juveniles. We performed histological and immunohistochemical studies on the knee joint cartilage in 5-week-old rats after treatment with 600 or 1,800 mg of sparfloxacin/kg of body weight. Treatment with single or multiple oral doses of 600 mg of sparfloxacin/kg was not sufficient to induce joint cartilage lesions. However, five of eight rats treated with a single oral dose of 1,800 mg of sparfloxacin/kg of body weight showed typical cartilage lesions in the femoral part of the knee joint. The concentrations of the drug in plasma measured 0.25, 0.75, 1.5, 3, 6, 12, and 24 h after the administration of an oral dose of 600 mg of sparfloxacin/kg were 6.3 ± 1.8, 9.2 ± 1.7, 9.6 ± 2.7, 13.0 ± 1.8, 12.3 ± 1.6, 3.4 ± 0.4, and 0.30 ± 0.20 mg/liter, respectively (mean ± standard deviation [SD];n = 5 to 6 per group). The concentrations in plasma measured 0.75, 1.5, 3, 6, 24, and 48 h after the administration of an oral dose of 1,800 mg of sparfloxacin/kg were 10.9 ± 1.5, 15.9 ± 1.6, 19.1 ± 1.7, 14.9 ± 3.1, 4.1 ± 0.6, and 0.46 ± 0.37 mg/liter, respectively (mean ± SD;n = 3 to 4 per group). The concentrations of sparfloxacin in joint cartilage were significantly higher at all time points studied (114.8 ± 80, 99.4 ± 31.5, 84.9 ± 16.8, 44.4 ± 13.9, and 14.2 ± 4.8 mg of sparfloxacin/kg at 1.5, 3, 6, 24, and 48 h after the administration of 1,800 mg/kg, respectively). The range of concentrations in bone were similar to the range of concentrations in cartilage (peak, 115 ± 12 mg/kg after 3 h). Our data indicate that chondrotoxic doses of sparfloxacin in juvenile rats are approximately 300 times higher than the doses of sparfloxacin used therapeutically (1,800 versus approximately 6 mg/kg of body weight), but due to species differences in kinetics, concentrations in plasma differ by a factor of only approximately 15. More data on quinolone concentrations in cartilage from animals and humans could provide a better basis for a reasonable risk assessment.

Download Full-text

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.46.6.1755-1759.2002 ◽

2002 ◽

Vol 46 (6) ◽

pp. 1755-1759 ◽

Cited By ~ 10

Author(s):

Edith Lozo ◽

Kai Riecke ◽

Rudolf Schwabe ◽

Jürgen Vormann ◽

Ralf Stahlmann

Keyword(s):

Synergistic Effect ◽

Magnesium Deficiency ◽

Peak Plasma ◽

Pediatric Population ◽

Standard Diet ◽

Joint Cartilage ◽

Deficient Diet ◽

Cartilage Lesions ◽

Oral Doses ◽

And Cartilage

ABSTRACT 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 Mg2+-deficient diet were significantly lower than those in the controls. The concentration in plasma from animals on an Mg2+-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.

Download Full-text

Effects of the Des-F(6)-Quinolone Garenoxacin (BMS-284756), in Comparison to Those of Ciprofloxacin and Ofloxacin, on Joint Cartilage in Immature Rats

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.46.10.3320-3322.2002 ◽

2002 ◽

Vol 46 (10) ◽

pp. 3320-3322 ◽

Cited By ~ 15

Author(s):

Eva Maria Kappel ◽

Mehdi Shakibaei ◽

Akintunde Bello ◽

Ralf Stahlmann

Keyword(s):

Body Weight ◽

Peak Plasma ◽

Joint Cartilage ◽

Once Daily ◽

Cartilage Lesions ◽

Human Risk ◽

Immature Rats ◽

Pediatric Use

ABSTRACT We did not observe signs of chondrotoxicity in immature rats treated orally with garenoxacin (BMS-284756) at doses up to five times 600 mg/kg of body weight or with ciprofloxacin, whereas ofloxacin induced typical cartilage lesions. The peak plasma garenoxacin concentration was 25.5 mg/liter after administration of a dose of 600 mg/kg once daily for 5 days. Assuming that this model is predictive of human risk, BMS-284756 and ciprofloxacin should be more suitable for pediatric use than ofloxacin.

Download Full-text

Effects of magnesium deficiency on joint cartilage in immature Beagle dogs: immunohistochemistry, electron microscopy, and mineral concentrations

Archives of Toxicology ◽

10.1007/s002040050010 ◽

2000 ◽

Vol 73 (10-11) ◽

pp. 573-580 ◽

Cited By ~ 12

Author(s):

R. Stahlmann ◽

S. Kühner ◽

M. Shakibaei ◽

J. Flores ◽

J. Vormann ◽

...

Keyword(s):

Electron Microscopy ◽

Magnesium Deficiency ◽

Joint Cartilage ◽

Beagle Dogs ◽

Mineral Concentrations

Download Full-text

Fresh Osteochondral Allograft Transplantation: A Suitable Option for the Treatment of Patellofemoral Joint Cartilage Lesions in the Young Patient

Journal of Transplantation Technologies & Research ◽

10.4172/2161-0991.1000168 ◽

2016 ◽

Vol 06 (04) ◽

Author(s):

Luiz Felipe Ambra ◽

Jack Farr ◽

Andreas H Gomoll

Keyword(s):

Young Patient ◽

Patellofemoral Joint ◽

Osteochondral Allograft ◽

Joint Cartilage ◽

Cartilage Lesions ◽

Allograft Transplantation ◽

Fresh Osteochondral Allograft

Download Full-text

Diminished Ciprofloxacin-Induced Chondrotoxicity by Supplementation with Magnesium and Vitamin E in Immature Rats

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01175-06 ◽

2007 ◽

Vol 51 (3) ◽

pp. 1022-1027 ◽

Cited By ~ 13

Author(s):

Kerstin Pfister ◽

Dago Mazur ◽

Jürgen Vormann ◽

Ralf Stahlmann

Keyword(s):

Vitamin E ◽

Wistar Rats ◽

Diet Group ◽

Standard Diet ◽

Joint Cartilage ◽

Cartilage Lesions ◽

Immature Rats ◽

Group A ◽

Group B ◽

Group D

ABSTRACT Quinolone-induced chondrotoxicity in juvenile rats and multiple other species has been demonstrated previously. Identical damages can be induced in immature rats by feeding them a magnesium-deficient diet. The objective of the present study was to investigate whether, in reverse, oral supplementation with magnesium, vitamin E, or both can diminish the typical quinolone-induced arthropathy in juvenile Wistar rats. Four groups of 12 (6 male, 6 female) 24-day-old Wistar rats were each fed either normal feed (group A), a vitamin E-enriched diet (group B), a magnesium-enriched diet (group C), or a diet enriched with both vitamin E and magnesium (group D) for 10 days. All rats received two subcutaneous ciprofloxacin doses of 600 mg/kg of body weight on postnatal day 32. Two days later, the rats were sacrificed and cartilage samples from knee joints were examined under a light microscope for the presence of typical quinolone-induced joint cartilage lesions. In addition, magnesium, calcium, and vitamin E concentrations in cartilage and plasma were determined. In the samples from rats fed a normal diet (group A), 17 quinolone-induced joint cartilage lesions were observed. In groups fed an enriched diet, the incidence of specific lesions (n) was significantly lower: group B, n = 10 (41% reduction compared to the incidence for group A; P < 0.05); group C, n = 6 (65% reduction; P < 0.01); and group D, n = 3 (82% reduction; P < 0.01). In comparison to the standard diet, diets with magnesium and vitamin E supplementation resulted in significantly higher magnesium and vitamin E concentrations in plasma and articular cartilage. Supplementation with magnesium and vitamin E alone or in combination may relevantly diminish joint cartilage lesions induced by quinolones in immature rats, with an additive effect of combined supplementation. The data further support the proposed pathomechanism of quinolone-induced arthropathy and the crucial role of magnesium in immature joint cartilage.

Download Full-text