Morphological investigation of cavity formation in articular cartilage induced by ofloxacin in rats

Kato, Michiyuki; Onodera, Toshiyuki

doi:10.1016/0272-0590(88)90275-8

Cited by 78 publications

(51 citation statements)

References 15 publications

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“…111 vitro, quinolones have inhibited DNA synthesis by nuclei and mitochondria of lymphoid cells by interfering with the activity of topoisomerase I1 (3, 9). The authors of ultrastructural studies, however, have implicated mechanisms for necrosis of chondrocytes that involved mitochondria1 swelling (8, 31) and cytoplasmic vacuolation (8,20). Because degeneration and necrosis of chondrocytes occurred very early in the development of the arthropathy, 'additional studies on the effects of fluoroquinolones on the metabolism of chondrocytes appear warranted.…”

Section: Resultsmentioning

confidence: 99%

Morphologic and Biochemical Changes in Articular Cartilages of Immature Beagle Dogs Dosed with Difloxacin

1992

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Quinolones are efficacious antibacterial compounds, but they have been associated with arthralgia in human patients; experimentally, they have caused lesions in articular cartilages of immature animals. The earliest morphologic and biochemical changes induced in articular-epiphyseal cartilage complexes by difloxacin, a fluoroquinolone, were investigated in 27 3-month-old Beagle dogs that were dosed orally with the drug at 300 m u k g body weight per day. Paraffin-embedded sections of humeral and femoral heads that were stained with either hematoxylin and eosin or toluidine blue and fast green were evaluated histologically, and lesions were scored according to established criteria. Although morphologic changes were not observed in cartilages of the control dogs or of the treated dogs in the 24-hr group, the severity of lesions, as represented by mean scores for lesions, increased during the 36-48 hr after dosing. The initial morphologic change, observed in cartilages from the treated dogs of the 36-and the 48-hr groups, was necrosis ofchondrocytes that was rapidly followed by disruption of extracellular matrix and formation of fissures. Although glycosaminoglycan was aggregated along the margins of fissures, its concentration was not reduced in cartilages of any group of treated dogs. Collagen, however, was depleted from the cartilages of the dogs that were euthanized 36 or 48 hr after the first dose of difloxacin. Because degenerative changes were observed ultrastructurally in chondrocytes by 24 hr in a previous study, it was concluded that collagen was lost from affected cartilages as an early sequel to the degeneration of chondrocytes.

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Section: Resultsmentioning

confidence: 99%

Morphologic and Biochemical Changes in Articular Cartilages of Immature Beagle Dogs Dosed with Difloxacin

1992

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“…Okazaki et al [14] have reported pharmacokinetics of ofloxacin in dogs differ from that in rats, suggesting species difference. This implied that there was species specificity even in the arthropathic dose of the drug [9,10].…”

Section: Disscusionmentioning

confidence: 99%

“…However, quinolones have been reported to induce arthropathy in juvenile animals such as mice [12], rats [4,9,10], rabbits [11], dogs [3,5,8,20], nonhuman primates [17] and others [1,2] as a class effect of these derivatives. Among these species, the juvenile dog is thought to be most susceptible to articular cartilage lesions [6,19,20].…”

mentioning

confidence: 99%

A Non-Arthropathic Dose and Its Disposition Following Repeated Oral Administration of Ofloxacin, a New Quinolone Antimicrobial Agent, to Juvenile Dogs.

Yabe

Murakami

Nishida

et al. 2001

The Journal of Veterinary Medical Science

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ABSTRACT. A non-arthropathic dose and disposition of ofloxacin, a potent new quinolone antimicrobial agent, were assessed in male juvenile (3-month-old) dogs, when administered orally at 5, 10 and 20 mg/kg/day once daily for 8 consecutive days. Ofloxacin concentrations in sera and articular cartilages were analyzed by high-performance liquid chromatography (HPLC). Macroscopically, arthropathy characterized by fluid-filled vesicles in articular surface of the humerus and femur was observed in animals receiving 10 and 20 mg/kg/day of ofloxacin, but not in those given 5 mg/kg/day. At 20 mg/kg/day, arthropathy of comparable severity also occurred on day 2. Microscopically, the cavity formation in the middle zone of the articular cartilage was first identified and then necrotic chondrocytes were found numerous around the cavity, followed by appearance of chondrocyte clusters. In pharmacokinetics, peak serum concentration (C max ) and area under the concentrations (AUC 0-24 ) were increased in a dose-dependent manner. However, no remarkable differences in these two parameters were noted between a single and repeated treatments, suggesting no accumulation of the drug. The articular ofloxacin concentration 2 hr after treatment was approximately 1.8 (day 2) to 2.0 times (day 8) higher than the serum concentration. Based on these results, a non-arthropathic dose of ofloxacin in male juvenile dogs following an 8-day treatment is considered to be 5 mg/kg/ day, and its C max , AUC 0-24 and articular cartilage concentrations 2 hr after treatment were 3.4 µg/ml, 35.1 µg⋅hr/ml and 7.0 µg/g, respectively, under these experimental conditions. Thus, arthropathy due to ofloxacin may be predicted by monitoring serum drug concentration. KEY WORDS: arthropathy, juvenile dog, non-arthropathic dose, ofloxacin, pharmacokinetics.J. Vet. Med. Sci. 63(8): 867-872, 2001 New quinolone antimicrobial agents (quinolones) are widely used in clinical fields because of their broad spectra and bactericidal activity. However, quinolones have been reported to induce arthropathy in juvenile animals such as mice [12], rats [4, 9, 10], rabbits [11], dogs [3, 5, 8, 20], nonhuman primates [17] and others [1, 2] as a class effect of these derivatives. Among these species, the juvenile dog is thought to be most susceptible to articular cartilage lesions [6,19,20].In our previous report [23], the arthropathic lesion due to ofloxacin was observed only in juvenile dogs, despite the fact that the drug concentration in the synovial fluid and articular cartilage of immature dogs (3-month-old) was equal to or lower than those in mature dogs (18-month-old). Kato and coworkers [10] have indicated that metabolically active immature chondrocytes are more sensitive to the effects of a quinolone, compared with inactive mature cells in the ex vivo study using 3 H-thymidine. Moreover, they have demonstrated that the initial target of the drug for the induction of arthropathy is the DNA synthesis of chondrocytes. Supporting this hypothesis, several DNA synthesis inhibito...

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“…Morphologic, immunohistochemical, and biochemical changes caused in articular cartilages by quinolones have been described in various species (2,3,7,11). Chondrocyte degeneration and necrosis, along with matrix rarefaction and increased staining for fibronectin, are followed by formation of overt fissures in the extracellular matrix and loss of collagen and proteoglycans.…”

Section: Introductionmentioning

confidence: 99%

“…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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Morphological investigation of cavity formation in articular cartilage induced by ofloxacin in rats

Cited by 78 publications

References 15 publications

Morphologic and Biochemical Changes in Articular Cartilages of Immature Beagle Dogs Dosed with Difloxacin

Morphologic and Biochemical Changes in Articular Cartilages of Immature Beagle Dogs Dosed with Difloxacin

A Non-Arthropathic Dose and Its Disposition Following Repeated Oral Administration of Ofloxacin, a New Quinolone Antimicrobial Agent, to Juvenile Dogs.

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

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