Chondrotoxicity of quinolones in vivo and in vitro

Hildebrand, H.; Kempka, G.; Schlüter, G.; Schmidt, Mathias V.

doi:10.1007/bf01977402

Cited by 34 publications

(23 citation statements)

References 17 publications

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“…Together, the results of the present study suggest that fluoroquinolone-induced tendinopathies occur by the same pathophysiological pathways as those described for cartilage (12,24). Previous reports suggested compromised mitochondrial activity, and a precocious stimulation of the oxidative metabolism within immature articular chondrocytes was also described (11,33), with both of these resulting in the generation of reactive oxygen species.…”

Section: Discussionsupporting

confidence: 82%

Pefloxacin-Induced Achilles Tendon Toxicity in Rodents: Biochemical Changes in Proteoglycan Synthesis and Oxidative Damage to Collagen

Simonin

Gégout-Pottie

Minn

et al. 2000

Antimicrob Agents Chemother

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Despite a relatively low incidence of serious side effects, fluoroquinolones and the fluoroquinolone pefloxacin have been reported to occasionally promote tendinopathy that might result in the complication of spontaneous rupture of tendons. In the present study, we investigated in rodents the intrinsic deleterious effect of pefloxacin (400 mg/kg of body weight) on Achilles tendon proteoglycans and collagen. Proteoglycan synthesis was determined by measurement of in vivo and ex vivo radiosulfate incorporation in mice. Collagen oxidative modifications were measured by carbonyl derivative detection by Western blotting. An experimental model of tendinous ischemia (2 h) and reperfusion (3 days) was achieved in rats. Biphasic changes in proteoglycan synthesis were observed after a single administration of pefloxacin, consisting of an early inhibition followed by a repair-like phase. The depletion phase was accompanied by a marked decrease in the endogenous serum sulfate level and a concomitant increase in the level of sulfate excretion in urine. Studies of ex vivo proteoglycan synthesis confirmed the in vivo results that were obtained. The decrease in proteoglycan anabolism seemed to be a direct effect of pefloxacin on tissue metabolism rather than a consequence of the low concentration of sulfate. Pefloxacin treatment for several days induced oxidative damage of type I collagen, with the alterations being identical to those observed in the experimental tendinous ischemia and reperfusion model. Oxidative damage was prevented by coadministration of N-acetylcysteine (150 mg/kg) to the mice. These results provide the first experimental evidence of a pefloxacin-induced oxidative stress in the Achilles tendon that altered proteoglycan anabolism and oxidized collagen.Fluoroquinolones are widely used in clinical practice because of their excellent antibacterial activity, wide spectrum of activity, and high degree of bioavailability. These antibiotics are generally considered well tolerated, although quinoloneinduced chondropathy has been observed in young animals of several species (3,4,9,31).Since 1992, tendinopathy has been described as another side effect in patients treated with fluoroquinolones, with the tendinopathy sometimes resulting in the rupture of the tendon. The cause of this rare (Յ1%) (7) but severe complication remains unexplained (13,14,28). Probably both because of the large number of prescriptions for pefloxacin and because of the high level of diffusion of pefloxacin into tissue, pefloxacin has been the subject of several reports on such secondary effects, and the Achilles tendon seems to be especially vulnerable to fluoroquinolone-promoted tendinopathy (14). The low incidence of this tendon-damaging effect suggests that it may result from some intrinsic effects of fluoroquinolones that could be realized as a result of certain factors, such as age, sex (the male-to-female ratio of those affected is 3:1), concomitant corticosteroid therapy, especially in renal graft patients (27), duration of treatment (26...

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Section: Discussionsupporting

confidence: 82%

Pefloxacin-Induced Achilles Tendon Toxicity in Rodents: Biochemical Changes in Proteoglycan Synthesis and Oxidative Damage to Collagen

Simonin

Gégout-Pottie

Minn

et al. 2000

Antimicrob Agents Chemother

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“…LVFX is therefore thought to affect the mitochondrial function of cultured chondrocytes, leading to impaired production of ATP. Concerning the effect of quinolones on mitochondrial functions of chondrocytes, Hildebrand et al (14) used a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assay to show that quinolones inhibit mitochondrial dehydrogenase activity in cultured chondrocytes of dog articular cartilage. Hayem et al (13) reported that oral administration of OFLX and pefloxacin increased the respiratory burst of chondrocytes in juvenile rabbits, suggesting the generation of reactive oxygen species.…”

Section: Discussionmentioning

confidence: 99%

“…On the basis of their findings, Stahlmann et al suggested that a possible mechanism of this quinolone chondrotoxicity may be impairment of mitochondrial DNA metabolism. Against this, recent in vitro and ex vivo studies have shown that the synthesis of proteoglycans and collagen and the mitochondrial function of chondrocytes are susceptible to inhibition in the presence of quinolones (7,13,14,26). Meanwhile, Stahlmann et al (28) subsequently reported another hypothesis, namely, that by forming stable chelate complexes with magnesium, quinolones may affect the electrolyte balance, impair the function of integrins, and cause degeneration of the matrix, thereby leading to severe damage of articular cartilage.…”

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confidence: 99%

Effect of levofloxacin on glycosaminoglycan and DNA synthesis of cultured rabbit chondrocytes at concentrations inducing cartilage lesions in vivo

Kato

Takada

Ogawara

et al. 1995

Antimicrob Agents Chemother

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We investigated the toxic effect of levofloxacin (LVFX), a quinolone antibacterial agent, on cartilage by examining aspects of its in vivo toxicokinetics and effect on the function of cultured chondrocytes of the femoral articular cartilage from juvenile New Zealand White rabbits. Repeated administration of LVFX (100 mg/kg) orally for 7 days induced focal necrosis and superficial erosion in the articular cartilage of the femoral condyle, but 30 mg/kg did not. Concentrations of LVFX in the cartilage were highest at the first sampling point (30 min) after a single administration, being 4.93 and 12.2 g/g in the 30-and 100-mg/kg groups, respectively. The arthropathic concentration of LVFX in the cartilage was then shown to be 12.2 g/g or more. For an in vitro study, chondrocytes were separated from the articular cartilage of the rabbit femoral condyle and cultured for 7 days until confluence. 35SO 4 uptake by cultured chondrocyte sheets was most susceptible to LVFX, decreasing at drug concentrations of 5 g/ml or more in 24-and 48-h cultures but not in a 72-h culture. Furthermore, 3 H-thymidine uptake was decreased at concentrations of 10 g/ml or more in a 48-h culture but not in 24-and 72-h cultures. Rhodamine 123 accumulation was susceptible to inhibition in cultured chondrocytes at an LVFX concentration of 10 g/ml or more. These results suggest that LVFX inhibits glycosaminoglycan synthesis initially and DNA synthesis and mitochondrial function secondarily at actual arthropathic concentrations in cultured rabbit chondrocytes but that these changes are reversible and not enough to kill the cells.Adverse effects of quinolone antibacterial drugs, including arthralgia, joint swelling, arthropathy, and arthritis, have been reported at incidences of less than 0.5% in healthy volunteers and juvenile and adult patients (17). Quinolones are well known to induce cavitation in the articular cartilage of juvenile rats, rabbits, guinea pigs, dogs, marmosets, and crab-eating monkeys but not in that of adults; of these species, dogs are thought to be most susceptible to this chondrotoxicity (4,5,11,12,15,16,24,25,27,29,31). However, the relationship between the adverse clinical effects of these drugs and their toxic lesions in laboratory animals has not been clarified.The initial changes in quinolone-induced toxicity in the articular cartilage of juvenile animals are thought to occur in chondrocytes (6,8,19) or in the matrix (4). In our previous ex vivo study, ofloxacin (OFLX) inhibited the uptake of 3 H-thymidine and 35 SO 4 by the articular cartilage of juvenile rats 12 h after oral administration of a single large dose (20). Considering the inhibitory effect of the drug on topoisomerase II of mammalian cells, we then speculated that the initial target of OFLX in its induction of cartilage damage was the DNA synthesis of chondrocytes. Histopathological examinations by Stahlmann et al. (29) and Burkhardt et al. (6,8) after administration of OFLX and difloxacin revealed mitochondrial swelling and distention of the rough endopla...

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“…In vitro studies with human lymphocytes exposed to enrofloxacin (ENR) and ciprofloxacin revealed an increase in the chromosomal aberrations, detected as chromatid and chromosome breaks and gaps (Gorla et al, 1999). FQs have been reported to cause neonatal alterations in articulation cartilages, bone growth and tendons, both in humans and animals (Patterson, 1991;Gough et al, 1992;Hildebrand et al, 1993;Forster et al, 1996;Simonin et al, 1999;Stahlmann, 2003;Lemus et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Assessment of the genotoxicity of quinolone and fluoroquinolones contaminated soil with the Vicia faba micronucleus test

Khadra¹,

Pinelli²,

Lacroix³

et al. 2012

Ecotoxicology and Environmental Safety

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, et al.. Assessment of the genotoxicity of quinolone and fluoroquinolones contaminated soil with the Vicia faba micronucleus test. Ecotoxicology and Environmental Safety, Elsevier, 2012, 76, pp.187-192. <10.1016/j.ecoenv.2011 a b s t r a c tThe genotoxicity of quinolone and fluroquinolones was assessed using the micronucleus (MN) test on Vicia faba roots by direct contact exposure to a solid matrix. Plants were exposed to quinolones (nalidixic acid) and fluoroquinolones (ciprofloxacin and enrofloxacin) alone or mixed with artificially contaminated soils. Four different concentrations of each of these antibiotics were tested (0.01, 0.1, 1 and 10 mg/Kg) for nalidixic acid and (0.005, 0.05, 0.5 and 5 mg/Kg) for ciprofloxacin and enrofloxacin. These antibiotics were also used in mixture. Exposure of Vicia faba plants to each antibiotic at the highest two concentrations showed significant MN induction. The lowest two concentrations had no significant genotoxic effect. The mixture of the three compounds induced a significant MN induction whatever the mixture tested, from 0.02 to 20 mg/Kg. The results indicated that a similar genotoxic effect was obtained with the mixture at 0.2 mg/Kg in comparison with each molecule alone at 5-10 mg/Kg. Data revealed a clear synergism of these molecules on Vicia faba genotoxicity.

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Chondrotoxicity of quinolones in vivo and in vitro

Cited by 34 publications

References 17 publications

Pefloxacin-Induced Achilles Tendon Toxicity in Rodents: Biochemical Changes in Proteoglycan Synthesis and Oxidative Damage to Collagen

Pefloxacin-Induced Achilles Tendon Toxicity in Rodents: Biochemical Changes in Proteoglycan Synthesis and Oxidative Damage to Collagen

Effect of levofloxacin on glycosaminoglycan and DNA synthesis of cultured rabbit chondrocytes at concentrations inducing cartilage lesions in vivo

Assessment of the genotoxicity of quinolone and fluoroquinolones contaminated soil with the Vicia faba micronucleus test

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