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

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

Toxicology and Applied Pharmacology

Volume 51, Issue 1, October 1979, Pages 177-187

https://doi.org/10.1016/0041-008X(79)90020-6 Get rights and content

Abstract

Oxolinic acid and pipemidic acid were administered orally to young beagle dogs for 14 days. Dogs receiving oxolinic acid were hyperactive throughout the study and showed transient hindlimb stiffness on Day 12. In contrast, dogs treated with pipemidic acid exhibited marked suppression of spontaneous activity and by Day 4 were unable to stand and ambulated painfully. Both compounds induced gross alterations of the articular cartilage in major synovial joints, including solitary or multiple vesicles and erosions. Histopathologically, these changes were characterized by cartilage matrix rarefaction, cavitations, cartilage fibrillation, and chondrocyte clustering predominantly in the intermediate zone. Hemorrhagic synovitis was a coincident finding in pipemidic-acid-treated dogs. Using lesion incidence and a scoring system which provided an overall estimation of both gross and microscopic findings, the arthropathic index was higher in dogs receiving pipemidic acid, thus demonstrating the greater arthropathogenic potential of this chemical. Lowered serum alkaline phosphatase values paralleled the arthropathies in each group.

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Fluoroquinolones are an important class of antimicrobials, given their broad spectrum of activity (including gram-negative, gram-positive, and atypical organisms), good tissue penetration, and oral bioavailability42,43; however, their use in children is generally discouraged ,given the arthropathy seen in juvenile animals in experimental trials.44 Preclinical studies of quinolones in juvenile beagle dogs revealed articular cartilage damage in weight-bearing joints.45–47 There have been reports of elderly patients developing quinolone-associated tendinitis and tendon rupture, most commonly in the Achilles tendon.46,48
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TNF/TNFR<inf>1</inf> pathway and endoplasmic reticulum stress are involved in ofloxacin-induced apoptosis of juvenile canine chondrocytes
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Therefore, research on QN chondrotoxicity is helpful for clinical risk evaluation of QNs or for strategies to prevent adverse effects associated with these valuable antimicrobials. In regard to the chondrotoxicity of QNs, some researchers believed that QNs suppressed the activities of DNA topoisomerase of chondrocytes, and interfered with the synthesis and decomposition of cartilage substances such as glycosaminoglycan, collagen and protein (Gough et al., 1979). Later, studies showed that QN-induced chondrotoxicity was characterized by chondrocyte apoptosis (Lim et al., 2008; Sheng et al., 2007).
Quinolones cause obvious cartilaginous lesions in juvenile animals by chondrocyte apoptosis, which results in the restriction of their use in pediatric and adolescent patients. Studies showed that chondrocytes can be induced to produce TNFα, and the cisternae of the endoplasmic reticulum in quinolone-treated chondrocytes become dilated. We investigated whether TNF/TNFR₁ pathway and endoplasmic reticulum stress (ERs) are involved in ofloxacin (a typical quinolone)-induced apoptosis of juvenile canine chondrocytes.
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Among the toxicities of QNs, one major disadvantage is their chondrotoxicity potential in juvenile animals, such as rats (Kato and Onodera, 1988), dogs (Burkhardt et al., 1992), rabbits (Machida et al., 1990), nonhuman primates (Stahlmann et al., 1990), and others (Gough et al., 1992). This toxicity is manifest as lameness, blistering, ulcerative erosion, or cavitation of the articular cartilage of the weight-bearing joints and chondrocyte loss and matrix degeneration (Gough et al., 1979; Kato and Onodera, 1988). Dosage needed to induce cartilage damage in juvenile dogs falls in the therapeutic range.
Quinolones (QNs)-induced arthropathy is an important toxic side-effect in immature animals leading to the restriction of their therapeutic use in pediatrics. Ofloxacin, a typical QN, was found to induce the chondrocytes apoptosis in the early phase (12–48 h) of arthropathy in our previous study. However, the exact mechanism(s) is unclear. Microencapsulated juvenile rabbit joint chondrocytes, a three-dimensional culture system, is utilized to perform the present study. Ofloxacin, at a therapeutically relevant concentration (10 μg/ml), disturbs the interaction between β1 integrin and activated intracellular signaling proteins at 12 h, which is inhibited when supplementing Mg^2 +. Intracellular reactive oxygen species (ROS) significantly increases in a time-dependent manner after exposure to ofloxacin for 12–48 h. Furthermore, ofloxacin markedly enhances the level of activated Rac1 and epidermal growth factor receptor (EGFR) phosphorylation, and its inhibition in turn reduces the ROS production, apoptosis and Rac1 activation. Silencing Nox2, Rac1 or supplementing Mg^2 + inhibits ROS accumulation, apoptosis occurrence and EGFR phosphorylation induced by ofloxacin. However, depletion of Nox2, Rac1 and inhibition of EGFR do not affect ofloxacin-mediated loss of interaction between β1 integrin and activated intracellular signaling proteins. In addition, ofloxacin also induces Vav2 phosphorylation, which is markedly suppressed after inactivating EGFR or supplementing Mg^2 +. These results suggest that ofloxacin causes Nox2-mediated intracellular ROS production by disrupting the β1 integrin function and then activating the EGFR-Vav2-Rac1 pathway, finally resulting in apoptosis within 12–48 h exposure. The present study provides a novel insight regarding the potential role of Nox-driven ROS in QNs-induced arthropathy.
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Juvenile canine drug-induced arthropathy: Clinicopathological studies on articular lesions caused by oxolinic and pipemidic acids

Abstract

Lancet

Toxicol. Lett.

Antibacterial drugs today. I

Drugs.

Cinoxacin induced arthropathy in juvenile beagle dogs

Toxicol. Appl. Pharmacol.

The reaction of articular cartilage to injury and osteoarthritis

N. Engl. J. Med.