Immunohistochemistry of Articular Cartilage from Immature Beagle Dogs Dosed with Difloxacin

Burkhardt, John E.; Förster, Christian; Lozo, Edith; Hill, Michael A.; Stahlmann, Ralf

doi:10.1177/019262339702500508

Cited by 15 publications

(11 citation statements)

References 26 publications

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“…Moreover, in many in vitro and ex vivo studies, the cartilage of various animal species has exhibited inhibition of synthesis of either collagen or glycosaminoglycans 28,29,50,51,[54][55][56][57] or proteoglycan and DNA 28,[50][51][52]56 . An increase in fibronectin staining is observed in the vicinity of the cavity in the articular cartilage of juvenile dogs and rats receiving difloxacin and ofloxacin, respectively 41,42 . A g e s p e c i f i c s u s c e p t i b i l i t y t o q u i n o l o n e chondrotoxicity-Feeding a magnesium-deficient diet to rats induces cartilage lesions in animals between 3 and 5 weeks of age, which correlates well with the ages sensitive to quinolone chondrotoxicity, but not of other ages.…”

Section: Cavity Formationmentioning

confidence: 99%

“…Slightly reduced expression of αv integrin on chondrocytes is exhibited in juvenile dogs receiving difloxacin in vivo 42 , and the expression of other integrins are also decreased in ofloxacintre ated mouse chondrocytes in vitro 4 3 -4 5 . W hen chondrocytes from juvenile rabbit joint cartilage are cultured with ofloxacin in alginate microspheres, β 1 -integrin expression is primarily reduced, and this causes subsequent changes in the extracellular signal-regulated kinase 1/2 / mitogen-activated protein kinase signaling pathway, resulting in caspase-8-dependent apoptosis of chondrocytes; supplementation with Mg 2+ blocks the changes in integrin and apoptosis 46 .…”

Section: Cavity Formationmentioning

confidence: 99%

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Chondrotoxicity of Quinolone Antimicrobial Agents

Kato

2008

J Toxicol Pathol

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Quinolone antimicrobial agents induce two types of histological changes in the articular cartilage of synovial joints in immature, but not mature, laboratory animals. The first is cavity formation in the middle zone of the articular cartilage in animals of all species examined so far, and this can be induced by a single or several daily doses. The second is osteochondrotic lesions in the caudal femoral condyles of rats when subchronic or chronic treatment is started at a juvenile age, but there seems to be only one reference for this effect. The development process of cavity formation is as follows. Degeneration and necrosis of chondrocytes are first observed, and the surrounding matrix becomes edematous with demasked collagen fibrils and decreased safranin O stainability. A flat cleft or cavity is then formed in the edematous cartilage, and erosion is sometimes produced by detachment of the cavity outer wall. The potency of quinolones to form chelate complexes with Mg 2+ is discussed as causal for cavity formation. This could lead to Mg 2+ deficiency in the cartilage, resulting in integrin alteration and further radical formation that can finally induce cartilage lesions. On the other hand, an early change of osteochondrosis is a thickened middle zone of the articular cartilage with a thinned deep zone. The thickened cartilage protrudes into the epiphysis and prevents age-dependent thinning of the cartilage. In advanced cases, fissures are formed in the bottom of the thickened cartilage, and extension of the fissures to the cartilage surface induces detachment of the cartilage, subchondral bone necrosis and fibrotic lesions in the marrow space. The lesions are considered to be caused by quinolone-induced inhibition of the differentiation of chondrocytes in the middle zone into those in the deep zone. For chondrotoxicity in juvenile animals, the pediatric use of quinolones is generally contraindicated, but whether or not chondrotoxicity could really occur in pediatric patients is still controversial. (J Toxicol Pathol 2008; 21: 123-131)

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Section: Cavity Formationmentioning

confidence: 99%

Section: Cavity Formationmentioning

confidence: 99%

Chondrotoxicity of Quinolone Antimicrobial Agents

Kato

2008

J Toxicol Pathol

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“…154 Lectins, by virtue of their glycoconjugate-binding properties, also represent useful reagents for histochemical characterization of cartilage, particularly as lectin-binding affinity of extracellular glycoconjugates may relate to different functions within growth plate cartilage. 159,160 Cartilage: degeneration 159,160 Cartilage: degeneration…”

Section: Technical Considerationsmentioning

confidence: 99%

“…173 The pathology of quinolone-induced articular changes has been well documented in juvenile beagle dogs, as these animals appear particularly susceptible. 159 The pathogenesis of this change in juvenile dogs is obscure, although it presumably represents a toxic action of these compounds on cartilage or on the metabolism of the chondrocyte of young animals. 164,169 Macroscopic examination of affected joints shows varying degrees of vesiculation, bullae development and detachment of a superficial layer from the surface of articular cartilage.…”

Section: Drug-induced Degenerationmentioning

confidence: 99%

Musculoskeletal System

Greaves

2012

Histopathology of Preclinical Toxicity Studies

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“…Although quinolone-induced arthropathy has not been proven to occur in humans (4), a wide variety of laboratory animal species are sensitive to the effect, including mice (12), rats (9,11), dogs (2,3,9), marmosets (20), guinea pigs (1), rabbits (8), and ferrets (6). The occurrence of quinolone arthropathy is limited to juvenile animals with the exception of pefloxacin, which produces characteristic lesions in both skeletally immature and mature dogs (5).…”

Section: Introductionmentioning

confidence: 99%

Effects of Nalidixic Acid on Hamster Knee Cartilage Morphology and Synovial Fluid Composition

Burkhardt¹,

Eskra

Clemo³

et al. 1999

Toxicol Pathol

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Quinolone-induced changes were studied in the knee joints of 4-wk-old female hamsters given intraperitoneal doses of either nalidixic acid (400 mg/kg body weight) or vehicle on days 0 and 1. After euthanasia on day 4, synovial fluid was collected for cytologic evaluation and for analysis of concentrations of hyaluronan, proteoglycans, total protein, and collagen as hydroxyproline. Slides of formalin-fixed decalcified tissues were stained with hematoxylin-eosin or safranin O for histologic scoring of lesion severity. Nine of 10 hamsters treated with nalidixic acid had fissures within articular cartilage of the femur and reduced safranin O staining of matrix indicative of loss of proteoglycans. Synovial membranes from affected joints, however, were not inflamed. Synovial fluid cell counts and cytomorphology were unaffected by treatment. In synovial fluid from 5 of 10 treated hamsters, proteoglycans were elevated by more than 2 SDs above the control group, and individual animal levels correlated with the histologic severity score (r2 = 0.36; p = 0.02). The hyaluronan content of the synovial fluid from treated hamsters was mildly but significantly elevated ( p = 0.005), and the histologic severity score again correlated with individual animal levels ( r 2 = 0.42; p = 0.01). Hydroxyproline was unaffected by treatment. Although synovial fluid changes and histologic changes were correlated on a group basis, interanimal variability was significant and the magnitude of biochemical changes were far smaller than those that occur during inflammation. Changes in synovial fluid composition are not sufficiently robust to predict cartilage changes in individual animals.

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Immunohistochemistry of Articular Cartilage from Immature Beagle Dogs Dosed with Difloxacin

Cited by 15 publications

References 26 publications

Chondrotoxicity of Quinolone Antimicrobial Agents

Chondrotoxicity of Quinolone Antimicrobial Agents

Musculoskeletal System

Effects of Nalidixic Acid on Hamster Knee Cartilage Morphology and Synovial Fluid Composition

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