Histologic and Histochemical Changes in Articular Cartilages of Immature Beagle Dogs Dosed with Difloxacin, a Fluoroquinolone

Burkhardt, John E.; Hill, Michael A.; Carlton, William W.; Kesterson, J. W.

doi:10.1177/030098589002700303

Cited by 113 publications

(79 citation statements)

References 22 publications

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“…The gross, histologic, and histochemical features of the early stage lesions in the AECC of immature Beagle dogs, dosed orally with difloxacin at 300 mgl kg body weight, have been described (7). The lesions were first observed as fissures within the intermediate zone of AECC at predilection sites that innot developed 24 hr after a single dose, but disruption of matrix and necrosis of chondrocytes were observed within the AECC of predilection sites at 48 hr (i.e., after 2 daily doses of difloxacin).…”

Section: Introduc~ionmentioning

confidence: 99%

“…Fixed bone and cartilage from the humeral and femoral heads were cut with a coping saw, perpendicular to the articular surface, into 5-mm-thick slabs that included AECC and epiphyseal bone. Slabs of bone and cartilage were decalcified in 10% formic acid (5-7 days), washed in tap water for 24 hr, dehydrated in graded alcohols; cleared in chloroform, and embedded in a mixture of parafin and low-polymer resin (7). Sections of tissue were cut on a rotary microtome at a thickness of 6 pm and stained with hematoxylin and eosin for evaluation of chondrocytes.…”

Section: Introduc~ionmentioning

confidence: 99%

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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: Introduc~ionmentioning

confidence: 99%

Section: Introduc~ionmentioning

confidence: 99%

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

1992

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“…Macroscopic examination focused on the articular cartilages in the humerus and femur. The regional area of these articular cartilages was highly susceptible to quinolone-induced arthropathy in juvenile dogs [3,20]. Assessment was made first for fluidfilled vesicle formation or local erosion in the articular cartilages, after which the surface layers of hyaline cartilage in the right humerus and femur were scraped off without contaminating bone tissues for determination of the drug concentration.…”

Section: Drugs and Experimental Designmentioning

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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“…The shortterm temporal effects of the fluoroquinolone difloxacin (at 300 mg/kg body weight) on articular cartilages in growing dogs have been described by Burkhardt et al using light microscopic (5), electron microscopic (6), and biochemical (4) methods. Results of these studies implicate the chondrocyte rather than the extracellular matrix as the component of cartilage initially sensitive to the arthropathic effect of difloxacin.…”

Section: Introductionmentioning

confidence: 99%

Immunohistochemistry of Articular Cartilage from Immature Beagle Dogs Dosed with Difloxacin

et al. 1997

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Histologic and Histochemical Changes in Articular Cartilages of Immature Beagle Dogs Dosed with Difloxacin, a Fluoroquinolone

Cited by 113 publications

References 22 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.

Immunohistochemistry of Articular Cartilage from Immature Beagle Dogs Dosed with Difloxacin

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