Ultrastructural changes induced by the des-F(6)-quinolone garenoxacin (BMS-284756) and two fluoroquinolones in Achilles tendon from immature rats

Abstract

Garenoxacin is a des-(6)-fluoroquinolone exhibiting a comparatively low chondrotoxic potential in juvenile animals. We studied the effects of the drug on Achilles tendons in immature Wistar rats treated by oral intubation once daily (1) for 5 consecutive days from postnatal week 4 onward at doses of 0 (vehicle), 200 and 600 mg/kg body weight (b wt), and (2) for 21 consecutive days from postnatal day 4 onward at doses of 0 (vehicle), 80, 240 or 300 mg/kg b wt; ofloxacin or ciprofloxacin were used as comparators. Achilles tendon specimens were studied by electron microscopy. In comparison with vehicle-treated controls, ultrastructural changes were detectable in all samples from the garenoxacin-, ofloxacin-, or ciprofloxacin-treated rats (one animal per group). We found degenerative changes such as multiple vacuoles and large vesicles in the cytoplasm of tenocytes that resulted from swelling and dilatation of cell organelles (mitochondria, endoplasmic reticulum), densified nuclei and clumped chromatin; furthermore, cells that detached from the extracellular matrix, a general decrease of the fibril diameter and an increase in the distance between the collagenous fibrils were recognizable. The degree of changes increased with increasing doses. It remains unclear what these findings mean with respect to a possible risk in juvenile patients treated with garenoxacin or the other quinolones, but our results underline the fact that, in principle, this des-(6)-fluoroquinolone also has the potential to cause changes in connective tissue structures.

Oral toxicity of pefloxacin, norfloxacin, ofloxacin and ciprofloxacin: comparison of biomechanical and histopathological effects on Achilles tendon in rats

“…Ciprofloxacin increased protease activity and inhibited both cell proliferation and the synthesis of matrix ground substance, when incubated with canine Achilles tendon and paratenon specimens in culture (Williams et al, 2000). Degenerative changes (multiple vacuoles, large vesicles) in the cytoplasm of tenocytes that resulted from swelling and dilatation of cell organelles, densified nuclei and clumped chromatin, cell detachment from the extracellular matrix, a general decrease of the fibril diameter and an increase in the distance between the collagenous fibrils were detected in Achilles tendons of garenoxacin-, ofloxacin-, or ciprofloxacin-treated immature Wistar rats (Shakibaei and Stahlmann, 2003). Similar ultrastructural changes were observed in Achilles tenocytes of gemifloxacin-, ofloxacin-, and ciprofloxacin-treated Sprague Dawley rats (Bae et al, 2006).…”

Effect of topical fluoroquinolones on the expression of matrix metalloproteinases in the cornea

“…[22-26] The clinical significance of these findings revolve around two main questions: how is the expression of these matrix metalloproteinase increased after the application of topical fluoroquinolone eye drops? and how significant are the eye drop preservatives at low concentration in stimulating MMP expression in the cornea?…”

Investigational new drugs for the treatment of resistant pneumococcal infections

“…However, high doses of garenoxacin administered daily for 5 days in Winstar rats that were 4 weeks old resulted in adverse effects on the Achilles tendon [62]. Achilles tendon specimens were studied by electron microscopy in comparison with vehicle-treated controls and ultrastructural changes were detectable in all of the samples from the garenoxacin-, ofloxacin-or ciprofloxacin-treated rats.…”