title: Quinolone-induced arthropathy in the neonatal mouse. Morphological analysis of articular lesions produced by pipemidic acid and ciprofloxacin.
abstract: Quinolone antibiotics are extensively utilized in antimicrobial chemotherapy. However, quinolone treatment in developing adolescents of several animal species is associated with acute arthropathy of the weight-bearing joints. Although arthropathy has rarely been observed following quinolone therapy in man, the toxicity observed in immature animals has resulted in restricted use of these drugs in children and pregnant women. Therefore, identification of novel quinolone antibiotics which do not cause arthropathy is highly desirable. This task would be facilitated by a bioassay of cartilage toxicity which utilizes small quantities of test material and has greater sensitivity than current toxicity assays. This study evaluated the utility of neonatal mice as a potential bioassay of quinolone-induced joint toxicity. Seven-day-old CF-1 mice (8-10/dose group) were treated subcutaneously with either pipemidic acid (50, 400, or 3150 mg/kg/day) for 7 or 14 days or ciprofloxacin (50 or 200 mg/kg/day) for 5, 7, or 14 days. Lameness was observed only after high-dose pipemidic acid treatment for 2-7 days. Histopathological assessment of the principal weight-bearing joints (knee, elbow, and multiple articulations in the fore- and hind-feet) revealed a lesion characterized by chondrocyte loss, matrix degeneration, and erosion of the articular cartilage in mice treated with pipemidic acid at 400 or 3150 mg/kg/day for 7 days or ciprofloxacin at 200 mg/kg/day for 5 days. Mice treated for 14 days with 400 mg/kg/day pipemidic acid demonstrated a lower incidence of lesions than mice treated for 7 days, suggesting the potential for reversibility during ongoing treatment. The results suggest that neonatal mice are sensitive to quinolone-induced arthropathy, but less so than previously reported for adolescent dogs. It is concluded that the neonatal mouse may be an appropriate screening system for identifying novel quinolones devoid of cartilage toxicity; however, follow-up studies with select compounds in a more sensitive species, such as the dog, are encouraged.
authors.affiliation: Department of Investigative Toxicology, Upjohn Company, Kalamazoo, Michigan 49001, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Linseman
authors.forename: L A
authors.initials: LA
authors.lastname: Hampton
authors.forename: D G
authors.initials: DG
authors.lastname: Branstetter
mesh_terms: D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D000890:Anti-Infective Agents / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D002358:Cartilage, Articular / Q000473:pathology*; D002939:Ciprofloxacin / Q000633:toxicity*; D005260:Female; D005528:Foot / Q000473:pathology; D007592:Joint Diseases / Q000139:chemically induced* / Q000473:pathology; D051379:Mice; D010876:Pipemidic Acid / Q000633:toxicity*; D011247:Pregnancy; D015363:Quinolones / Q000633:toxicity*
chemical_list: D000890:Anti-Infective Agents; D015363:Quinolones; D002939:Ciprofloxacin; D010876:Pipemidic Acid