Characterization of fluoroquinolone-induced Achilles tendon toxicity in rats: comparison of toxicities of 10 fluoroquinolones and effects of anti-inflammatory compounds.
Fluoroquinolone antibacterial agents have been reported to induce tendon lesions in juvenile rats. In the present study, we characterized fluoroquinolone-induced Achilles tendon lesions by comparing the effects of 10 fluoroquinolones and examining the potential of one of these antimicrobial agents, pefloxacin, to induce tendon lesions when coadministered with one of nine anti-inflammatory compounds. Among the 10 fluoroquinolones tested, fleroxacin and pefloxacin were the most toxic, inducing lesions at a dose of 100 mg/kg of body weight or more, while lomefloxacin, levofloxacin, and ofloxacin or sparfloxacin and enoxacin induced lesions at 300 mg/kg or more and 900 mg/kg, respectively. In contrast, norfloxacin, ciprofloxacin, and tosufloxacin had no effect even at the high dose of 900 mg/kg. The severity of the Achilles tendon lesions appeared to correlate with the structure of the substituent at the seventh position. Furthermore, pefloxacin-induced tendon lesions were inhibited by coadministration with dexamethasone and N-nitro-L-arginine methyl ester. Phenidone (1-phenyl-3-pyrazolidinone) and 2-(12-hydroxydodeca-5,10-diynyl)3,5,6-trimethyl-1,4-benzoqui none (AA861) also decreased the incidence of tendon lesions. In contrast, catalase, dimethyl sulfoxide, indomethacin, pyrilamine, and cimetidine did not modify these tendon lesions. These results suggest that nitric oxide and 5-lipoxigenase products partly mediate fluoroquinolone-induced tendon lesions.
Kashida
Y
Y
Drug Safety Research Laboratory, Daiichi Pharmaceutical Co. Ltd., Edogawa, Tokyo, Japan.
Kato
M
M
D042462:4-Quinolones; D000125:Achilles Tendon / Q000187:drug effects* / Q000473:pathology; D000284:Administration, Oral; D000818:Animals; D000890:Anti-Infective Agents / Q000037:antagonists & inhibitors / Q000633:toxicity*; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D004347:Drug Interactions; D024841:Fluoroquinolones; D008297:Male; D015363:Quinolones / Q000037:antagonists & inhibitors / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D015366:Pefloxacin
D042462:4-Quinolones; D000890:Anti-Infective Agents; D000893:Anti-Inflammatory Agents; D024841:Fluoroquinolones; D015363:Quinolones; D015366:Pefloxacin