Chondrotoxicity of ciprofloxacin in immature beagle dogs: immunohistochemistry, electron microscopy and drug plasma concentrations.
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.
Stahlmann
R
R
Institut für Klinische Pharmakologie und Toxikologie, Abteilung Toxikologie, Universitätsklinikum Benjamin Franklin, Freie Universität Berlin, Garystr. 5, 14195 Berlin, Germany.
Kühner
S
S
Shakibaei
M
M
Schwabe
R
R
Flores
J
J
Evander
S A
SA
van Sickle
D C
DC
D000818:Animals; D000890:Anti-Infective Agents / Q000097:blood / Q000633:toxicity*; D002358:Cartilage, Articular / Q000737:chemistry / Q000187:drug effects* / Q000473:pathology; D019902:Chondrocytes / Q000187:drug effects* / Q000648:ultrastructure; D002851:Chromatography, High Pressure Liquid; D002939:Ciprofloxacin / Q000097:blood / Q000633:toxicity*; D003094:Collagen / Q000032:analysis; D004285:Dogs; D018870:Endoplasmic Reticulum, Rough / Q000187:drug effects / Q000648:ultrastructure; D005260:Female; D005269:Femur / Q000187:drug effects / Q000473:pathology; D005353:Fibronectins / Q000032:analysis; D019084:Fluorescent Antibody Technique, Indirect; D016023:Integrins / Q000032:analysis; D007719:Knee Joint / Q000737:chemistry / Q000187:drug effects* / Q000473:pathology; D008297:Male; D008854:Microscopy, Electron; D008928:Mitochondria / Q000187:drug effects / Q000648:ultrastructure; D018675:Toxicity Tests
D000890:Anti-Infective Agents; D005353:Fibronectins; D016023:Integrins; D002939:Ciprofloxacin; D003094:Collagen