Linseman D A, Hampton L A, Branstetter D G
Department of Investigative Toxicology, Upjohn Company, Kalamazoo, Michigan 49001, USA.
Fundam Appl Toxicol. 1995 Nov;28(1):59-64. doi: 10.1006/faat.1995.1146.
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.
喹诺酮类抗生素在抗菌化疗中被广泛应用。然而，在几种动物的发育中的青少年中进行喹诺酮治疗与负重关节的急性关节病有关。虽然在人类中喹诺酮治疗后很少观察到关节病，但在未成熟动物中观察到的毒性导致这些药物在儿童和孕妇中的使用受到限制。因此，非常需要鉴定不会引起关节病的新型喹诺酮类抗生素。利用少量测试材料且比当前毒性试验具有更高灵敏度的软骨毒性生物测定法将有助于完成这项任务。本研究评估了新生小鼠作为喹诺酮诱导的关节毒性潜在生物测定法的效用。7日龄的CF-1小鼠（每组8 - 10只）皮下注射吡哌酸（50、400或3150 mg/kg/天）7天或14天，或环丙沙星（50或200 mg/kg/天）5天、7天或14天。仅在高剂量吡哌酸治疗2 - 7天后观察到跛行。对主要负重关节（膝、肘以及前后足的多个关节）的组织病理学评估显示，在以400或3150 mg/kg/天的剂量接受吡哌酸治疗7天的小鼠或以200 mg/kg/天的剂量接受环丙沙星治疗5天的小鼠中，出现了以软骨细胞丢失、基质变性和关节软骨侵蚀为特征的病变。以400 mg/kg/天的剂量接受吡哌酸治疗14天的小鼠病变发生率低于治疗7天的小鼠，这表明在持续治疗过程中病变具有可逆性。结果表明，新生小鼠对喹诺酮诱导的关节病敏感，但比先前报道的青春期犬的敏感性低。结论是，新生小鼠可能是鉴定无软骨毒性的新型喹诺酮的合适筛选系统；然而，鼓励对选定化合物在更敏感的物种（如犬）中进行后续研究。
