Bourgeois Thomas, Delezoide Anne-Lise, Zhao Wei, Guimiot Fabien, Adle-Biassette Homa, Durand Estelle, Ringot Maud, Gallego Jorge, Storme Thomas, Le Guellec Chantal, Kassaï Behrouz, Turner Mark A, Jacqz-Aigrain Evelyne, Matrot Boris
Inserm, U1141, Robert Debré Hospital, APHP, 75019, Paris, France; Denis Diderot-Paris 7 University, Robert Debré Hospital, Paris, France.
Inserm, U1141, Robert Debré Hospital, APHP, 75019, Paris, France; Denis Diderot-Paris 7 University, Robert Debré Hospital, Paris, France; Department of Developmental Biology, Robert Debré Hospital, APHP, Paris, France.
Regul Toxicol Pharmacol. 2016 Feb;74:161-9. doi: 10.1016/j.yrtph.2015.11.002. Epub 2015 Nov 26.
Ciprofloxacin, a broad-spectrum antimicrobial agent belonging to the fluoroquinolone family, is prescribed off-label in infants less than one year of age. Ciprofloxacin is included in the European Medicines Agency priority list of off-patent medicinal products requiring evaluation in neonates. This evaluation is undergoing within the TINN (Treat Infections in Neonates) FP7 EU project. As part of the TINN project, the present preclinical study was designed to assess the potential adverse effects of Ciprofloxacin on neurodevelopment, liver and joints in mice. Newborn mice received subcutaneous Ciprofloxacin at 10, 30 and 100 mg/kg/day from 2 to 12 postnatal days. Peak plasma levels of Ciprofloxacin were in the range of levels measured in human neonates. We examined vital functions in vivo, including cardiorespiratory parameters and temperature, psychomotor development, exploratory behavior, arthro-, nephro- and hepato-toxic effects. We found no effect of Ciprofloxacin at 10 and 30 mg/kg/day. In contrast, administration at 100 mg/kg/day delayed weight gain, impaired cardiorespiratory and psychomotor development, caused inflammatory infiltrates in the connective tissues surrounding the knee joint, and moderately increased extramedullary hematopoiesis. The present study pleads for careful watching of cardiorespiratory and motor development in neonates treated with Ciprofloxacin, in addition to the standard surveillance of arthrotoxicity.
环丙沙星是一种属于氟喹诺酮类的广谱抗菌剂，在一岁以下婴儿中属于超说明书用药。环丙沙星被列入欧洲药品管理局需要在新生儿中进行评估的非专利药品优先清单。这项评估正在“TINN（新生儿感染治疗）”欧盟第七框架项目内进行。作为TINN项目的一部分，本临床前研究旨在评估环丙沙星对小鼠神经发育、肝脏和关节的潜在不良影响。新生小鼠在出生后第2天至12天接受10、30和100毫克/千克/天的皮下环丙沙星注射。环丙沙星的血浆峰值水平处于在人类新生儿中测得的水平范围内。我们检查了体内的重要功能，包括心肺参数和体温、精神运动发育、探索行为、关节、肾脏和肝脏毒性作用。我们发现10和30毫克/千克/天的环丙沙星没有影响。相比之下，100毫克/千克/天的给药延迟了体重增加，损害了心肺和精神运动发育，导致膝关节周围结缔组织出现炎症浸润，并适度增加了髓外造血。本研究呼吁在对使用环丙沙星治疗的新生儿进行标准的关节毒性监测之外，还要仔细观察其心肺和运动发育情况。
