Chondrotoxicity of ciprofloxacin in immature Beagle dogs: immunohistochemistry, electron microscopy and drug plasma concentrations

Abstract

The systemic effects of ciprofloxacin in immature Beagles were studied. Dogs of 10-11 weeks were dosed orally for 5 days with 0 (n=3), 30 (n=5) and 200 (n=5) mg ciprofloxacin/kg body wt. Plasma concentrations were measured by high-performance liquid chromatography (HPLC) 1 h after dosing (assuming to be peak concentrations). In view of the high doses used, the plasma concentrations were rather low and declined during the study period. For example, plasma concentrations in the high dose group were 6.6 +/- 0.9 mg/l (day 1), 3.9 +/- 1.4 mg/l (day 3), and 2.6 +/- 1.6 mg/l (day 5). In control dogs and in dogs treated with the low dose of ciprofloxacin no pathological changes were seen by light microscopy. However, cleft formation and erosions were observed in joint cartilage from two of five dogs treated with 200 mg/kg. It is noteworthy that despite the high dose used cartilage lesions were not detectable in all five dogs of this group by light microscopy. Using antibodies against cell membrane receptors (e.g. the alpha(5)beta(1)-integrin) or matrix components (fibronectin, collagen II) the articular cartilage effects were studied in detail by immunohistochemistry. The most sensitive alteration was an increase in fibronectin which was detectable in the vicinity of the lesions in cartilage samples from the group of dogs administered the high dose. No clear-cut changes were seen with the use of antibodies against other matrix components. Electron microscopy revealed typical alterations in chondrocytes from dogs treated with ciprofloxacin: e.g., swollen mitochondria and enlarged rough endoplasmic reticulum. These changes were much more pronounced in dogs from the high dose group than in dogs from the low dose group. Our main conclusion is that after oral administration ciprofloxacin exhibits rather low chondrotoxicity, even in the most sensitive species known to date. This correlates with the findings in humans that ciprofloxacin seems to be less chondrotoxic than pefloxacin or other quinolones.

Ciprofloxacin Induced Chondrotoxicity and Tendinopathy

“…Ciprofloxacin also affected the mean length of humora and femora leading to reduction in Limb length of rat pulps (Channa et al, 2008). The above reports could be consistent with the study of Stahlmann et al (2000) who reported that 200 mg kg −1 of Ciprofloxacin administered to immature Beagles induced cleft formation and erosion of joint cartilage. Male wistar rats exposed to 50mg kg −1 of Ciprofloxacin for 21 days inhibit fracture healing with decreased cartilage cellullarity and fibrous proliferation and matrix degeneration (Huddleston et al, 2000).…”

The effects of enrofloxacin on canine tendon cells and chondrocytes proliferation in vitro

“…Biochemical alterations were observed at both dose levels studied, but the low dose treatment (30 mg/kg) was not associated with clinical symptoms in four of five dogs; only at the higher dose were alterations in gait noticed in all treated dogs. Clear cut lesions in joint cartilage were detected in samples from only two of five dogs in the highdose ciprofloxacin group (200 mg/kg), as described elsewhere (Stahlmann et al 2000). In considering drug safety, it is a major concern that alterations to the pericellular matrix in tendons might be present without recognizable clinical effects until a major part of the matrix the organized collagens fibers is affected.…”

Effects of ciprofloxacin on joint cartilage in immature dogs immediately after dosing and after a 5-month treatment-free period

“…At the end of this treatment-free period and after the dogs had developed from juvenile to adult animals, a necropsy and histopathology investigation of weight-bearing joints was performed. This included the use of stains to investigate specifically the cartilage matrix, immunohistochemical demonstration of a 5 b 1 integrin and electron microscopy, which have been described as sensitive methods for the detection of quinolone-induced changes (Shakibaei et al 1995;Kuehner 2000;Stahlmann et al 2000). None of these animals showed any quinoloneinduced joint lesion.…”