Juvenile canine drug-induced arthropathy: Clinicopathological studies on articular lesions caused by oxolinic and pipemidic acids

Gough, A. W.; Barsoum, N. J.; Mitchell, Lorelie; McGuire, Edward J.; Iglesia, Felix A. de la

doi:10.1016/0041-008x(79)90020-6

Cited by 119 publications

(61 citation statements)

References 8 publications

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“…We have demonstrated that the development of tendon lesions were inhibited by coadministration of a steroidal anti-inflammatory drug (dexamethasone), a dual cyclooxygenase/lipoxygenage inhibitor (phenidone), a 5-lipoxygenase inhibitor (AA-861), or a nitric oxide inhibitor (N-nitro-Larginine methyl ester) (Kashida and Kato, in preparation). Supporting this result, we detected the elevated level of nitrate/nitrite in urine of juvenile rats after a single oral administration of PFLX (13 (6,14,29,32). The lesion seen in the present study was the same as those previously reported.…”

Section: Electron Microscopysupporting

confidence: 82%

“…Although its mechanisms are not completely understood, some suggested hypotheses include the involvement of mitochondrial dysfunction (2), interference of the drug with DNA metabolism (30), or interference with the extracellular matrix of joint cartilage by formation of quinolone-magnesium chelate complexes (5,27 Quinolones have been widely used. However, because of their toxic potential to the immature articular cartilage, which has been demonstrated in many animal species (2,6,7,14,16,26) …”

Section: Electron Microscopymentioning

confidence: 99%

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Toxic Effects of Quinolone Antibacterial Agents on the Musculoskeletal System in Juvenile Rats

Kashida

Kato

1997

Toxicol Pathol

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Quinolone antibacterial agents have adverse effects on the musculoskeletal system in humans, consisting mainly of myalgia and arthralgia, and additionally of tendon disorders and rhabdomyolysis. The present study was conducted to examine the toxic effects of quinolones on the musculoskeletal system in juvenile rats using light microscopy, 5-bromo-2'-deoxyuridine (BrdU) immunohistochemistry and electron microscopy. Single oral administration of 900 mg/kg pefloxacin (PFLX) or levofloxacin (LVFX) was found to induce lesions in the muscle + fascia, tendon + sheath, and synovial membrane, in addition to articular cartilage in the fore-and hindlimbs. Articular cartilage lesions were not necessarily associated with changes in the muscle, tendon, and synovial membrane, or the reverse. Among all lesions, the ankle and elbow showed the highest incidence and severity. Changes were more severe in the PFLX than in the LVFX group. Lesions in the muscle + fascia, tendon + sheath, and synovial membrane were similar and characterized by edema and increased number of mononuclear cells, many of which were positively stained with BrdU, as well as vascular endothelial cells in the Achilles tendon sheath and synovial membrane in the ankle. Electron microscopic examination revealed an increased number of fibroblasts and macrophages and collagen deposition in the matrix of the synovial membrane and tendon sheath. Capillary endothelial cells were hypertrophied, increased in number, and stratified. These results suggest that quinolones have toxic potentials in the muscle, tendon, and synovial membrane in addition to articular cartilage, and that local vascular hyperpermeability may contribute to the development of these lesions.

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Section: Electron Microscopysupporting

confidence: 82%

Section: Electron Microscopymentioning

confidence: 99%

Toxic Effects of Quinolone Antibacterial Agents on the Musculoskeletal System in Juvenile Rats

Kashida

Kato

1997

Toxicol Pathol

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“…7 Although pipemidic acid and nalidixic acid apparently induced lesions after 3 days of treatment, descriptions of lesions were sparse and In the majority of studies in which skeletally immature dogs were treated with quinolones, joints were examined after 7 or more days of treatment, and most descriptions were of chronic lesion^.^,'-^ Because of the paucity of information on the earliest changes associated with lesions in cartilages of dogs treated with quinolones, the present study was conducted to determine the distribution and morphologic features of the lesions caused by difloxacin, a fluoroquinolone. As the effects of quinolones on the extracellular matrix of articular cartilage have not been adequately reported in the dog, a histochemical technique was applied to samples of cartilage and bone in the present study.…”

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confidence: 99%

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

Burkhardt

Hill²,

Carlton³

et al. 1990

Vet Pathol

112

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Abstract. The histologic and histochemical features of quinolone-induced arthropathy were studied using 14 skeletally immature Beagle dogs (3 to 4 months old) dosed orally with difloxacin at 300 mg/kg body weight once daily for 1, 2, 5 , or 7 days. A placebo was given to eight other age-matched Beagle dogs that served as controls. A scoring technique that included lesion size and histologic features was used to determine the progression of lesions. Articular-epiphyseal cartilage complexes on the femoral and humeral heads and tibia1 tarsal bone were identified as predilection sites. Within predilection sites on femoral and humeral heads, lesions developed in specific areas. Lesions appeared within 2 days of the onset of treatment, and lesion scores increased with time. Grossly, the lesions were raised, fluid-filled vesicles on the articular surface. Histologic changes included vesicle formation with loss of proteoglycan, clumping of unmasked collagen, and degeneration and necrosis of chondrocytes. In lesions with higher scores, chondrocytes were often in clusters or they were undergoing metaplasia toward spindle-shaped cells. Although dissolution of matrix and necrosis of chondrocytes were typical of all lesions, smaller lesions had histologically normal chondrocytes adjacent to small vesicles. In sections stained with toluidine blue, proteoglycan was aggregated with collagen fibrils or was absent from the matrix adjacent to vesicles. Unique features, such as biomechanical forces, may predispose specific areas of articular cartilage to develop lesions.Key words: Arthropathy; articular cartilage; difloxacin; dog; fluoroquinolone.Despite the potential value of quinolone antibacterial compounds in treating infections caused by bacteria resistant to other antibacterial agents, the use of quinolones is restricted because of their toxic effects on articular-epiphyseal cartilage complexes. The use of quinolones in children and pregnant women (ie., the fetuses that they carry) is contraindicated, seemingly because of a report of arthralgia induced by nalidixic acid, a quinolone, in a 22-year-old woman. ' Additionally, laboratory evidence for quinolones causing lesions in articular cartilages of immature animals has prompted the need for caution in the use of these drugs in human beings with immature skeletons. Various reports have described the lesions produced in the articular cartilages of skeletally immature dogs and rats and other skeletally immature laboratory ani m a l~.~,~-~,~~-~~.~~ In general, gross lesions were fluid-filled vesicles that projected above the contour of the articular surface. Microscopically, lesions consisted of fissures within the intermediate zone of the articular cartilage. Along fissure margins, chondrocytes were necrotic in early lesions but formed clusters in chronic lesions undergoing repair. The matrix adjacent to fissures was disrupted, and collagen fibrils were clumped.In addition to lesions in articular cartilages, pipemidic acid and oxolinic acid caused synovitis in immature dogs.7...

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“…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].…”

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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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Juvenile canine drug-induced arthropathy: Clinicopathological studies on articular lesions caused by oxolinic and pipemidic acids

Cited by 119 publications

References 8 publications

Toxic Effects of Quinolone Antibacterial Agents on the Musculoskeletal System in Juvenile Rats

Toxic Effects of Quinolone Antibacterial Agents on the Musculoskeletal System in Juvenile Rats

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

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

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